This invention relates to substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors, to pharmaceutical compositions comprising such compounds, and to methods of using these compounds for treating viral infection.
Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS (Dagani, Chem. Eng. News, Nov. 23, 1987 pp. 41-49) involve administration of compounds such as 2xe2x80x2,3xe2x80x2-dideoxycytidine, trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, 1-b-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide, 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), and adriamycin that inhibit viral DNA synthesis; compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell; and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity, and bone marrow cytopenia.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of the infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford et al., J. Virol. 53 899 (1985); Katoh et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987).
Moore, Biochem. Biophys. Res. Commun., 159 420 (1989) discloses peptidyl inhibitors of HIV protease. Erickson, European Patent Application No. WO 89/10752 discloses derivatives of peptides which are inhibitors of HIV protease.
U.S. Pat. No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Pat. No. 4,644,055 discloses halomethyl derivatives of peptides as inhibitors of viral proteases. European Patent Application No. WO 87/07836 discloses L-glutamic acid gamma-monohydroxamate as an antiviral agent.
The ability to inhibit a viral protease provides a method for blocking viral replication and therefore a treatment for viral diseases, such as AIDS, that may have fewer side effects, be more efficacious, and be less prone to drug resistance when compared to current treatments.
The present invention concerns novel substituted cyclic carbonyls and derivatives thereof, which compounds are capable of inhibiting viral protease and which compounds are believed to serve as a means of combating viral diseases, such as AIDS. The substituted cyclic carbonyls and derivatives thereof of this invention provide significant improvements over protease inhibitors that are known in the art. A large number of compounds have been reported to be inhibitors of proteases, such as renin, but these have suffered from lack of adequate bioavailability and are thus not useful as therapeutic agents, particularly if oral administration is desired. This poor activity has been ascribed to the relatively high molecular weight of most protease inhibitors, to inadequate solubility properties, and to the presence of a number of peptide bonds, which are vulnerable to cleavage by mammalian proteases in vivo and which generally cause the molecules to be extensively bound in human serum. The substituted cyclic carbonyls and derivatives described herein have a distinct advantage in this regard, in that they do not contain peptide bonds, are of low molecular weight, and can be hydrophilic yet still inhibit the viral protease enzyme.
Additionally, known inhibitors of other non-HIV proteases do not inhibit HIV protease. The structure-activity requirements of such inhibitors differ from those of HIV protease inhibitors. The substituted cyclic carbonyls and derivatives of the invention are particularly useful as inhibitors of HIV protease and similar retroviral proteases.
The compounds of the invention are of low molecular weight and may, therefore, have good oral absorption properties in mammals.
This invention provides novel substituted cyclic carbonyl compounds and derivatives thereof, of formula (I) (described below) which are useful as inhibitors of Human Immunodeficiency Virus (HIV). The compounds of the present invention inhibit the HIV protease and thereby inhibit HIV replication. The present invention also includes pharmaceutical compositions containing such compounds of formula I, and methods of using such compounds for the inhibition of HIV in a sample containing HIV, and methods of using such compounds for the treatment of HIV infection in a patient.
The present invention also includes methods of inhibiting HIV or treating HIV infection by administering a compound of formula (I) in combination with one or more second therapeutic agents selected from other inhibitors of HIV and/or therapeutic agents for the treatment of HIV-mediated disease conditions.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of formula I, for the treatment of HIV infection.
This invention provides novel substituted cyclic carbonyl compounds and derivatives thereof, of formula (I) (described below) which are useful as inhibitors of Human Immunodeficiency Virus (HIV). The compounds of the present invention inhibit the HIV protease and thereby inhibit HIV replication. The present invention also includes pharmaceutical compositions containing such compounds of formula I, and methods of using such compounds for the inhibition of HIV in a sample containing HIV, and methods of using such compounds for the treatment of HIV infection in a patient.
[1] There is provided by this invention a compound of the formula (I): 
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
R4 and R7 are independently selected from the following groups:
hydrogen;
C2-C8 alkyl substituted with 0-3 R11;
C2-C8 alkenyl substituted with 0-3 R11;
C2-C8 alkynyl substituted with 0-3 R11;
a C3-C14 carbocyclic ring system substituted with
0-3 R11 or 0-3 R12;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R12;
xe2x80x94OR13; xe2x80x94SR13; CO2R13;
R4A and R7A are independently selected from the following groups:
hydrogen;
C1-C4 alkyl substituted with 0-6 halogen or 0-3 C1-C2 alkoxy;
benzyl substituted with 0-6 halogen or 0-3 C1-C2 alkoxy;
xe2x80x94OR13; xe2x80x94SR13; CO2R13;
R4 and R4A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R12;
R7 and R7A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R12;
n is 0, 1, or 2;
R5 is selected from H; halogen; C1-C6 alkyl substituted with 0-3 R11; xe2x80x94N(R20)2; xe2x80x94SR20; or xe2x80x94OR20, xe2x80x94N3;
R6 is independently selected from: hydrogen, halogen, C1-C6 alkyl substituted with 0-3 R11, xe2x80x94N(R20)2, xe2x80x94SR20, or xe2x80x94OR21, xe2x80x94N3;
R5 and R6 can alternatively join to form an epoxide or aziridine ring; xe2x80x94OCH2SCH2Oxe2x80x94; xe2x80x94OC(xe2x95x90O)Oxe2x80x94; xe2x80x94OCH2Oxe2x80x94; xe2x80x94OC(xe2x95x90S)Oxe2x80x94; xe2x80x94OC(xe2x95x90O)C(xe2x95x90O)Oxe2x80x94; xe2x80x94OC(CH3)2Oxe2x80x94; xe2x80x94OC((CH2)3NH2)(CH3)Oxe2x80x94; xe2x80x94OC(OCH3)(CH2CH2CH3)Oxe2x80x94; xe2x80x94OS(xe2x95x90O)Oxe2x80x94; xe2x80x94NHC(xe2x95x90O)NHxe2x80x94; xe2x80x94OC(xe2x95x90O)NHxe2x80x94; xe2x80x94NHC(xe2x95x90O)Oxe2x80x94; xe2x80x94NHCH2Oxe2x80x94; xe2x80x94OCH2NHxe2x80x94; xe2x80x94NHC(xe2x95x90S)Oxe2x80x94; xe2x80x94OS(xe2x95x90O)NHxe2x80x94; xe2x80x94NHC(xe2x95x90O)C(xe2x95x90O)Oxe2x80x94; xe2x80x94OC(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94; xe2x80x94NHC(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94; xe2x80x94NHC(CH3)2Oxe2x80x94; xe2x80x94OC(CH3)2NHxe2x80x94 or any group that, when administered to a mammalian subject, cleaves to form a free dihydroxyl or diamino or hydroxyl and amino;
R5a is selected from hydrogen, halogen, C1-C6 alkyl, xe2x80x94N(R20)2, xe2x80x94SR20, or xe2x80x94OR20;
R6 a is selected from: hydrogen, halogen, C1-C6 alkyl, xe2x80x94N(R20)2, xe2x80x94SR20 or xe2x80x94OR21;
R5 and R5a can alternatively join to form xe2x95x90O, xe2x95x90S, or a ketal ring;
R6 and R6a can alternatively join to form xe2x95x90O, xe2x95x90S, or a ketal ring;
R20 and R21 are independently selected from:
hydrogen;
C1-C6 alkyl substituted with 0-3 R11;
C3-C6 alkoxyalkyl substituted with 0-3 R11;
C1-C6 alkylcarbonyl substituted with 0-3 R11;
C1-C6 alkoxycarbonyl substituted with 0-3 R11;
C1-C6 alkylaminocarbonyl substituted with 0-3 R11;
benzoyl substituted with 0-3 R12;
phenoxycarbonyl substituted with 0-3 R12;
phenylaminocarbonyl substituted with 0-3 R12; or
any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulfhydryl;
R11 is selected from one or more of the following:
H, keto, halogen, cyano, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, xe2x80x94CO2R13, xe2x80x94OC(xe2x95x90O)R13, xe2x80x94OR13, xe2x80x94S(O)mR13, xe2x80x94NHC(xe2x95x90NH)NHR13, xe2x80x94C(xe2x95x90NH)NHR13, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94NR14C(xe2x95x90O)R13, xe2x95x90NOR14, xe2x80x94NR14C(xe2x95x90O)OR14, xe2x80x94OC(xe2x95x90O)NR13R14, xe2x80x94NR13C(xe2x95x90O)NR13R14, xe2x80x94NR14SO2NR13R14, xe2x80x94NR14SO2R13, xe2x80x94SO2NR13R14, xe2x80x94OP(O)(OR13)2, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-C10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with xe2x80x94NR13R14, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, pyridylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, xe2x80x94OCH2CO2H, 2-(1-morpholino)ethoxy, azido, or xe2x80x94C(R14)xe2x95x90N(OR14);
1-3 amino acids linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus;
C3-C10 cycloalkyl substituted with 0-2 R12;
C1-C4 alkyl substitued with 0-2 R12 aryl(C1-C3 alkyl)-, substituted with 0-2 R12;
C2-C6 alkoxyalkyl-, substituted with 0-2 R12;
C1-C4 alkylcarbonyloxy substituted with 0-2 R12,
C6-C10 arylcarbonyloxy substituted with 0-2 R12,
a C5-C14 carbocyclic residue substituted with 0-3 R12;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R12;
R11A is selected from one or more of the following:
H, keto, halogen, cyano, xe2x80x94CH2N(R13A)R(14A), xe2x80x94N(R13A)R(14A), xe2x80x94CO2H, xe2x80x94OC(xe2x95x90O)(C1-C3 alkyl), xe2x80x94OH, C2-C6 alkoxyalkyl, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94OC(xe2x95x90O)NH2, xe2x80x94NHC(xe2x95x90O)NH2, xe2x80x94SO2NH2, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-C10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with xe2x80x94NH2, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, xe2x80x94OCH2CO2H, 2-(1-morpholino)ethoxy, azido, aryl(C1-C3 alkyl), a C5-C14 carbocyclic residue; a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system substituted with 0-3 R12A.
R12, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, xe2x80x94CO2H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, xe2x80x94OR13, C1-C4 alkyl substituted with xe2x80x94NR13R14, xe2x80x94NR13R14, C2-C6 alkoxyalkylene optionally substituted with xe2x80x94Si(CH3)3, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, xe2x80x94S(O)mR13, xe2x80x94SO2NR13R14, xe2x80x94NHSO2R14, xe2x80x94OCH2CO2R13, 2-(1-morpholino)ethoxy, xe2x80x94C(R14)xe2x95x90N(OR14); or
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
or R12 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or xe2x80x94NR13R14; or, when R12 is attached to a saturated carbon atom, it may be xe2x95x90O or xe2x95x90S; or when R12 is attached to sulfur it may be xe2x95x90O.
R12, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, xe2x80x94CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, xe2x80x94C(R14)xe2x95x90N(OR14);
R12A, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, xe2x80x94CO2H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, xe2x80x94OR13, C1-C4 alkyl substituted with xe2x80x94NH2, xe2x80x94NH2, xe2x80x94NHMe, C2-C6 alkoxyalkyl optionally substituted with Si(CH3)3, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, xe2x80x94S(O)mMe, xe2x80x94SO2NH2, xe2x80x94NHSO2Me, xe2x80x94OCH2CO2R13, 2-(1-morpholino)ethoxy, xe2x80x94C(xe2x95x90NOH)NH2; or
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
or R12A may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or xe2x80x94NH2; or, when R12A is attached to a saturated carbon atom, it may be xe2x95x90O or xe2x95x90S; or when R12 is attached to sulfur it may be xe2x95x90O.
R12A, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, xe2x80x94CH2NH2, xe2x80x94NH2, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, xe2x80x94CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, xe2x80x94C(xe2x95x90NOH)NH2;
R13 is selected from:
H;
phenyl substituted with 0-3 R11A;
benzyl substituted with 0-3 R11A;
C1-C6 alkyl substituted with 0-3 R11A;
C2-C4 alkenyl substituted with 0-3 R11A;
C1-C6 alkylcarbonyl substituted with 0-3 R11A;
C1-C6 alkoxycarbonyl substituted with 0-3 R11A;
C1-C6 alkylaminocarbonyl substituted with 0-3 R11A;
C3-C6 alkoxyalkyl substituted with 0-3 R11A;
an amine protecting group when R13 is bonded to N;
a hydroxy protecting group when R13 is bonded to O;
R14 is hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 groups selected from OH, C1-C4 alkoxy, halogen, NH2, xe2x80x94NH(C1-C4 alkyl), C1-C6 alkoxy, C2-C6 alkenyl, phenyl, benzyl, an amine protecting group when R14 is bonded to N, a hydroxy protecting group when R14 is bonded to O;
R13 and R14 can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(R15)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94;
R13A and R14A are independently selected from: H, C1-C6 alkyl;
R13A and R14A can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(R15)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94;
R15 is H or CH3;
m is 0, 1 or 2;
W is selected from:
xe2x80x94N(R22)C(xe2x95x90Z)N(R23)xe2x80x94;
xe2x80x94OC(xe2x95x90Z)Oxe2x80x94;
xe2x80x94N(R22)C(xe2x95x90Z)Oxe2x80x94;
xe2x80x94C(R25)(R26)C(xe2x95x90Z)C(R27)(R28)xe2x80x94;
xe2x80x94N(R22)C(xe2x95x90Z)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)C(xe2x95x90Z)Oxe2x80x94;
xe2x80x94N(R22)C(xe2x95x90Z)C(xe2x95x90Z)N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)C(F2)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)N(CH3)(O)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)N(OR29)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)C(xe2x95x90Z)Sxe2x80x94;
xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)N(R23)xe2x80x94;
xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)2N(R23)xe2x80x94;
xe2x80x94N(R22)P(xe2x95x90O)(R24a)N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)2C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)2N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90O)2Oxe2x80x94;
xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)Oxe2x80x94;
xe2x80x94C(R25)C(F2)C(xe2x95x90O)N(R23)xe2x80x94;
xe2x80x94C(R25)C(F2)S(xe2x95x90O)2N(R23)xe2x80x94;
xe2x80x94SC(xe2x95x90Z)xe2x80x94;
xe2x80x94C(R25)(R26)C(R34)(R35)C(R27)(R28)xe2x80x94;
xe2x80x94N(R22)C(R34)(R35)N(R23)xe2x80x94;
xe2x80x94Nxe2x95x90C(R36)N(R23)xe2x80x94;
xe2x80x94N+(R22)xe2x95x90C(R36)N(R23)xe2x80x94;
xe2x80x94N(R22)P(R24a)N(R23)xe2x80x94;
xe2x80x94C(xe2x95x90Z)xe2x80x94;
xe2x80x94P(xe2x95x90O)(R24a)xe2x80x94;
xe2x80x94S(xe2x95x90Zxe2x80x2)xe2x80x94;
xe2x80x94S(xe2x95x90Zxe2x80x2)2xe2x80x94;
xe2x80x94N(R22)C(xe2x95x90C(R36a)(R36b))N(R23)xe2x80x94
xe2x80x94N(R22)C(xe2x95x90Z)N(R23)C(xe2x95x90Z)xe2x80x94
wherein:
Z is O, S, NR24;
Zxe2x80x2 is O or NR24;
R22 and R23 are independently selected from the following:
hydrogen; xe2x80x94OR22a; xe2x80x94N(R22a)(R22b);
C1-C8 alkyl substituted with 0-3 R31;
C2-C8 alkenyl substituted with 0-3 R31;
C2-C8 alkynyl substituted with 0-3 R31;
a C3-C14 carbocyclic ring system substituted with 0-5 R31 or 0-5 R32;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R32;
R22a and R22b are independently selected from the following:
hydrogen;
C1-C8 alkyl substituted with 0-3 R31;
C2-C8 alkenyl substituted with 0-3 R31;
C2-C8 alkynyl substituted with 0-3 R31;
a C3-C14 carbocyclic ring system substituted with 0-5 R31 or 0-5 R32;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R32;
R24 is selected from: hydrogen; hydroxy; amino; C1-C4 alkyl; C1-C4 alkoxy; mono- or di-(C1-C6 alkyl)amino; cyano; nitro; benzyloxy; xe2x80x94NHSO2aryl, aryl being optionally substituted with (C1-C6)alkyl;
R24a is selected from: hydroxy; amino; C1-C4 alkyl; C1-C4 alkoxy; mono- or di-(C1-C6 alkyl)amino; cyano; nitro; benzyloxy; or phenoxy;
R25 and R27 are independently selected from the following:
hydrogen;
C1-C8 alkyl substituted with 0-3 R31;
C2-C8 alkenyl substituted with 0-3 R31;
C2-C8 alkynyl substituted with 0-3 R31;
a C3-C14 carbocyclic ring system substituted with 0-5 R31 or 0-5 R32;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R32;
xe2x80x94OR13; xe2x80x94SR13;
R26 and R28 are independently selected from:
hydrogen;
halogen;
C1-C4 alkyl substituted with 0-3 halogen or 0-3 C1-C2 alkoxy;
benzyl substituted with 0-3 halogen or 0-3 C1-C2 alkoxy;
xe2x80x94OR13; xe2x80x94SR13;
R29 is selected from:
hydrogen;
C1-C4 alkyl substituted with 0-3 halogen or 0-3 C1-C2 alkoxy;
benzyl substituted with 0-3 halogen or 0-3 C1-C2 alkoxy;
alternatively, R22, R25, or R26, independently, can join with R4 or R4A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R12, said heterocyclic ring containing 1-3 heteroatoms independently selected from N, S, or O; or
alternatively, R23, R27, or R28, independently, can join with R7 or R7A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R12, said heterocyclic ring containing 1-3 heteroatoms independently selected from N, S, or O; or
alternatively, R22, R25, R26, R23, R27, R28, R34, or R35 can join with R5 or R6 to form a 0- to 7-membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R12 and said bridge containing 0-3 heteroatoms independently selected from N, S, or O (i.e., a 0-membered bridge is formed when R22, R25, R26, R23, R27, R28, R34, or R35 are taken together with R5 or R6 to form a direct bond);
alternatively R28 or R23 can join with R7A to form a direct bond;
alternatively R26 or R22 can join with R4A to form a direct bond;
R31 is selected from one or more of the following:
keto, halogen, cyano, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, xe2x80x94CO2R13, xe2x80x94C(xe2x95x90O)R11, xe2x80x94OC(xe2x95x90O)R13, xe2x80x94OR13, C2-C6 alkoxyalkyl, xe2x80x94S(O)mR13, xe2x80x94NHC(xe2x95x90NH)NHR13, xe2x80x94C(xe2x95x90NH)NHR13, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94NR14C(xe2x95x90O)R13, xe2x95x90NOR14, xe2x80x94NR14C(xe2x95x90O)OR14, xe2x80x94OC(xe2x95x90O)NR13R14, xe2x80x94NR13C(xe2x95x90O)NR13R14, xe2x80x94NR13C(xe2x95x90S)NR13R14, xe2x80x94NR14SO2NR13R14, xe2x80x94NR14SO2R13, SO2NR13R14, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-C10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with xe2x80x94NR13R14, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, xe2x80x94OCH2CO2R13, 2-(1-morpholino)ethoxy, azido, xe2x80x94C(R14)xe2x95x90N(OR14); or
1-3 amino acids, linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus;
a C5-C14 carbocyclic residue substituted with 0-5 R32; or
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R32;
R32, when a substituent on carbon, is selected from one or more of the following:
phenethyl, phenoxy, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, hydrazide, oxime, boronic acid, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 alkylcarbonyloxy, xe2x80x94NHSO2R14, benzyloxy, halogen, 2-(1-morpholino)ethoxy, xe2x80x94CO2R13, hydroxamic acid, xe2x80x94CONR13NR13R14, cyano, sulfonamide, xe2x80x94CHO, C3-C6 cycloalkoxy, xe2x80x94NR13R14, xe2x80x94C(R14)xe2x95x90N(OR14), NO2, xe2x80x94OR13, xe2x80x94NR40R41, xe2x80x94SOmR13, xe2x80x94SOmNR13R14, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94OC(xe2x95x90O)NR13R14, xe2x80x94C(xe2x95x90O)R11, xe2x80x94OC(xe2x95x90O)R11, xe2x80x94OCO2R13, phenyl, xe2x80x94C(xe2x95x90O)NR13xe2x80x94(C1-C4 alkyl)xe2x80x94NR13R14, xe2x80x94C(xe2x95x90O)NR40R41, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C1-C4 haloalkynyl, or
xe2x80x94C(xe2x95x90O) NR13C(R11)2NR13R14;
xe2x80x94C(xe2x95x90O)NR13C(R11)2NR13CO2R13;
xe2x80x94C(xe2x95x90O)NR13xe2x80x94(C1-C4 alkyl)xe2x80x94NR13CO2R13;
xe2x80x94C(xe2x95x90O)N(R13)xe2x80x94(C1-C4 alkyl)xe2x80x94R11; or
xe2x80x94C(xe2x95x90O)C(R11)2NR13R14;
xe2x80x94C(xe2x95x90O)C(R11)2NR13CO2R13;
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13R14;
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13CO2R13; or
C1-C4 alkoxy substituted with 0-4 groups selected from: R11, C3-C6 cycloalkyl, xe2x80x94CO2R13, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94NR13R14 or OH;
C1-C4 alkyl substituted with 0-4 groups selected from: R11, xe2x95x90NR14, xe2x95x90NNR13C(xe2x95x90O)NR13R14, xe2x95x90NNR13C(xe2x95x90O)OR13, or xe2x80x94NR13R14;
C2-C4 alkenyl substituted with 0-4 R11;
C2-C4 alkynyl substituted with 0-4 R11;
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 R12;
or R32 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or xe2x80x94NR13R14; or, when R32 is attached to a saturated carbon atom, it may be xe2x95x90O, xe2x95x90S, xe2x95x90NOH; or when R32 attached to sulfur it may be xe2x95x90O.
R32, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, xe2x80x94CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, xe2x80x94C(R14)xe2x95x90N(OR14);
R34 is selected from:
hydrogen;
OR13;
SR13;
halogen;
N(R38)(R39)
C1-C6 alkyl substituted with 0-3 R11;
C1-C6 alkoxy substituted with 0-3 R11;
C1-C6 thioalkyl substituted with 0-3 R11;
R35 is selected from:
hydrogen;
OR13;
SR13;
halogen;
N(R38)(R39)
C1-C6 alkyl substituted with 0-3 R11;
C1-C6 alkoxy substituted with 0-3 R11;
C1-C6 thioalkyl substituted with 0-3 R11;
R34 and R35 can be taken together to form a ketal ring, a 3- to 8-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms independently selected from the group O, N, or S, said ring substituted with 0-5 R11;
R36 is selected from:
H
C1-C6 alkyl substituted with 0-3 R11;
xe2x80x94COR37;
xe2x80x94NR38R39;
xe2x80x94CN;
xe2x80x94NO2 
R37 is selected from:
hydrogen;
C1-C6 alkyl substituted with 0-3 R11;
hydroxyl;
C1-C6 alkoxy substituted with 0-3 R11;
xe2x80x94NR38R39;
R38 and R39 are independently selected from:
hydrogen;
C1-C6 alkyl substituted with 0-3 R11; or
an amine protecting group;
R40 is selected from: H, C1-C3 alkyl;
R41 is selected from:
xe2x80x94C(xe2x95x90O) NR13R14;
xe2x80x94C(xe2x95x90O) NR13NR13R14;
xe2x80x94C(xe2x95x90O)C(R11)2NR13R14;
xe2x80x94C(xe2x95x90O)C(R11)2NR13NR13R14;
xe2x80x94C(xe2x95x90O)C(R11)2NR13CO2R13;
xe2x80x94C(xe2x95x90O)H;
xe2x80x94C(xe2x95x90O)R11;
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13R14;
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13CO2R13;
1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus;
provided that:
R4, R4A, R7 and R7A are not all hydrogen;
when W is xe2x80x94OC(xe2x95x90Z)Oxe2x80x94, xe2x80x94SC(xe2x95x90Z)xe2x80x94, xe2x80x94C(xe2x95x90Z)xe2x80x94, xe2x80x94P(xe2x95x90O)(R24a)xe2x80x94, xe2x80x94S(xe2x95x90Zxe2x80x2)xe2x80x94 or xe2x80x94S(xe2x95x90Zxe2x80x2)2xe2x80x94, R4 and R7 are not hydrogen;
when R4, R4A are hydrogen, at least one of the following is not hydrogen: R22, R25, and R26.
[2] Preferred compounds include those compounds described above wherein:
when W is
xe2x80x94C(xe2x95x90Z)xe2x80x94;
xe2x80x94P(xe2x95x90O)(R24a)xe2x80x94;
xe2x80x94S(xe2x95x90Zxe2x80x2)2xe2x80x94;
then n is 1 or 2.
[3] Preferred compounds include those compounds described above wherein:
R4 and R7 are independently selected from the following groups:
hydrogen;
C1-C8 alkyl substituted with 0-3 R11;
C2-C8 alkenyl substituted with 0-3 R11;
C2-C8 alkynyl substituted with 0-3 R11;
C3-C8 cycloalkyl substituted with 0-3 R11;
C6-C10 bicycloalkyl substituted with 0-3 R11;
aryl substituted with 0-3 R12;
a C6-C14 partially unsaturated carbocyclic residue substituted with 0-3 R12;
a 5- to 6-membered heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R12;
R22 and R23 are independently selected from the following:
hydrogen;
C1-C8 alkyl substituted with 0-3 R31;
C2-C8 alkenyl substituted with 0-3 R31;
C2-C8 alkynyl substituted with 0-3 R31;
C3-C8 cycloalkyl substituted with 0-3 R31;
C6-C10 bicycloalkyl substituted with 0-3 R31;
aryl substituted with 0-5 R32;
a C6-C14 partially unsaturated carbocyclic residue substituted with 0-3 R32;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R32;
R25 and R27 are independently selected from the following:
hydrogen;
C1-C8 alkyl substituted with 0-3 R31;
C2-C8 alkenyl substituted with 0-3 R31;
C2-C8 alkynyl substituted with 0-3 R31;
C3-C8 cycloalkyl substituted with 0-3 R31;
C6-C10 bicycloalkyl substituted with 0-3 R31;
aryl substituted with 0-5 R32;
a C6-C14 partially unsaturated carbocyclic residue substituted with 0-3 R32;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R32.
[4] Preferred compounds of this invention are those compounds described above with the proviso that when:
W is xe2x80x94C(R25)(R26)C(xe2x95x90Z)C(R27)(R28)xe2x80x94; and
n=0; and
Z is O;
then R25, R26, R27, and R28 are not all H.
[5] Preferred compounds of this invention are those compounds described above with the proviso that when:
W is xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)C(R27)(R28)xe2x80x94; and
n=0; and
Zxe2x80x2 is O;
then R25, R26, R27, and R28 are not all H.
[6] Preferred compounds of this invention are those compounds described above with the proviso that when:
W is xe2x80x94C(R25)(R26)S(xe2x95x90Z)2C(R27)(R28)xe2x80x94; and
n=0; and
Zxe2x80x2 is O or NH;
then R25, R26, R27, and R28 are not all H.
[7] Preferred compounds of this invention are those compounds described above with the proviso that when:
W is xe2x80x94S(xe2x95x90O)xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94; and
n=1;
then R6 and R6a are not both H.
[8] Preferred compounds of this invention are those compounds described above with the proviso that when:
W is xe2x80x94C(R25)(R26)C(R34)(R35)C(R27)(R28)xe2x80x94; and
n=0; and
R34 or R35 are N(R38)(R39);
then R25, R26, R27, and R28 are not all H.
[9] Preferred compounds of this invention are compounds of the formula (I): 
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
R4 and R7 are independently selected from the following groups:
hydrogen;
C1-C4 alkyl substituted with 0-3 R11;
C3-C4 alkenyl substituted with 0-3 R11;
C3-C4 alkynyl substituted with 0-3 R11;
R4A and R7A are hydrogen;
R5 is selected from fluoro, xe2x80x94OR20, xe2x80x94N(R20)2;
R6 is independently selected from: hydrogen, fluoro or xe2x80x94OR21;
R5 and R6 can alternatively join to form an epoxide or aziridine ring; xe2x80x94OCH2SCH2Oxe2x80x94; xe2x80x94OS(xe2x95x90O)Oxe2x80x94; xe2x80x94OC(xe2x95x90O)Oxe2x80x94; xe2x80x94OCH2Oxe2x80x94; xe2x80x94OC(xe2x95x90S)Oxe2x80x94; xe2x80x94OC(xe2x95x90O)C(xe2x95x90O)Oxe2x80x94; xe2x80x94OC(CH3)2Oxe2x80x94; xe2x80x94OC(OCH3)(CH2CH2CH3)Oxe2x80x94; or any group that, when administered to a mammalian subject, cleaves to form a free dihydroxyl;
R5a is selected from hydrogen or fluoro;
R6a is selected from: hydrogen or fluoro;
R5 and R5a can alternatively join to form xe2x95x90O, xe2x95x90S, or a ketal ring;
R6 and R6a can alternatively join to form xe2x95x90O, xe2x95x90S, or a ketal ring;
R20 and R21 are independently selected from:
hydrogen;
C1-C6 alkylcarbonyl;
C1-C6 alkoxycarbonyl;
benzoyl; or
any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl;
R11 is selected from one or more of the following:
H, keto, halogen, cyano, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, xe2x80x94CO2R13, xe2x80x94OC(xe2x95x90O)R13, xe2x80x94OR13, C2-C4 alkoxyalkyl, xe2x80x94S(O)mR13, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl;
a C5-C14 saturated or partially unsaturated carbocyclic residue substituted with 0-3 R12;
aryl(C1-C3 alkyl)-, substituted with 0-2 R12;
aryl substituted with 0-3 R12; or
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R12;
R12, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, 2-(1-morpholino)ethoxy, xe2x80x94CO2H, hydroxamic acid, hydrazide, xe2x80x94C(R14)xe2x95x90N(OR14), cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, xe2x80x94OR13, C1-C4 alkyl substituted with xe2x80x94NR13R14, xe2x80x94NR13R14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, xe2x80x94S(O)mR13, xe2x80x94SO2NR13R14, xe2x80x94NHSO2R14; or
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
or R12 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or xe2x80x94NR13R14; or, when R12 is attached to a saturated carbon atom, it may be xe2x95x90O or xe2x95x90S; or when R12 is attached to sulfur it may be xe2x95x90O.
R12, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, xe2x80x94CO2H;
R13 is H, C1-C6 alkyl, C3-C6 alkoxyalkyl, C2-C4 alkenyl, phenyl, or benzyl;
R14 is OH, H, CF3, C1-C4 alkyl, C1-C4 alkoxy, NH2, C2-C4 alkenyl, phenyl, or benzyl;
R13 and R14 can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(R15)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94;
W is selected from:
xe2x80x94N(R22)C(xe2x95x90Z)N(R23)xe2x80x94;
xe2x80x94N(R22)C(xe2x95x90Z) Oxe2x80x94;
xe2x80x94C(R25)(R26)C(xe2x95x90Z)C(R27)(R28)xe2x80x94;
xe2x80x94N(R22)C(xe2x95x90Z)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)C(xe2x95x90Z)Oxe2x80x94;
xe2x80x94N(R22)C(xe2x95x90O)C(xe2x95x90O)N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)C(F2)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)N(CH3)(O)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)N(OR29)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)C(xe2x95x90Z)Sxe2x80x94;
xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)N(R23)xe2x80x94;
xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)2N(R23)xe2x80x94;
xe2x80x94N(R22)P(xe2x95x90O)(R24a)(N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)2C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)2N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90O)2Oxe2x80x94;
xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)Oxe2x80x94;
xe2x80x94C(R25)C(F2)C(xe2x95x90O)N(R23)xe2x80x94;
xe2x80x94C(R25)C(F2)S(xe2x95x90O)2N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)C(R34)(R35)C(R27)(R28)xe2x80x94;
xe2x80x94Nxe2x95x90C(R36)N(R23)xe2x80x94;
xe2x80x94N(R22) p(R24a)N(R23)xe2x80x94;
xe2x80x94C(xe2x95x90Z)xe2x80x94;
xe2x80x94P(xe2x95x90O)(R24a)xe2x80x94;
xe2x80x94S(xe2x95x90Zxe2x80x2)xe2x80x94;
xe2x80x94S(xe2x95x90Zxe2x80x2)2xe2x80x94;
wherein:
Z is O, S, Nxe2x80x94CN, Nxe2x80x94OH, Nxe2x80x94OCH3;
Zxe2x80x2 is oxygen:
R22 and R23 are independently selected from the following:
hydrogen;
C1-C8 alkyl substituted with 0-3 R31;
C3-C8 alkenyl substituted with 0-3 R31;
C3-C8 alkynyl substituted with 0-3 R31;
C3-C6 cycloalkyl substituted with 0-3 R31;
R24a is selected from xe2x80x94OH, C1-C4 alkoxy, mono- or di-(C1-C6 alkyl)amino;
R25 and R27 are independently selected from the following:
hydrogen;
C1-C8 alkyl substituted with 0-3 R31;
C2-C8 alkenyl substituted with 0-3 R31;
C3-C8 alkynyl substituted with 0-3 R31;
R26 and R28 are hydrogen or halogen;
R29 is selected from:
hydrogen;
C1-C2 alkyl substituted with 0-2 C1-C2 alkoxy;
benzyl substituted with 0-2 halogen or 0-2 C1-C2 alkoxy;
R31 is selected from one or more of the following:
keto, halogen, cyano, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, xe2x80x94CO2R13, xe2x80x94OC(xe2x95x90O)R13, xe2x80x94OR13, C2-C4 alkoxyalkyl, xe2x80x94S(O)mR13, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-C10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with xe2x80x94NR13R14, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, xe2x80x94OCH2CO2H, 2-(1-morpholino)ethoxy, xe2x80x94C(R14)xe2x95x90N(OR14); or
a C5-C14 saturated or partially unsaturated carbocyclic residue substituted with 0-3 R32;
aryl substituted with 0-3 R32; or
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R32;
R32, when a substituent on carbon, is selected from one or more of the following:
phenethyl, phenoxy, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, hydrazide, oxime, boronic acid, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 alkylcarbonyloxy, xe2x80x94NHSO2R14, benzyloxy, halogen, 2-(1-morpholino)ethoxy, xe2x80x94CO2R13, hydroxamic acid, xe2x80x94CONR13NR13R14, cyano, sulfonamide, xe2x80x94CHO, C3-C6 cycloalkoxy, xe2x80x94NR13R14, xe2x80x94C(R14)xe2x95x90N(OR14), xe2x80x94NO2, xe2x80x94OR13, xe2x80x94NR40R41, SOmNR13, xe2x80x94SOmNR13R14, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94OC(xe2x95x90O)NR13R14, xe2x80x94C(xe2x95x90O)R11, xe2x80x94OC(xe2x95x90O)R11, xe2x80x94OCO2R13, phenyl, xe2x80x94C(xe2x95x90O)NR13xe2x80x94(C1-C4 alkyl)xe2x80x94NR13R14, xe2x80x94C(xe2x95x90O)NR40R41, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, or
xe2x80x94C(xe2x95x90O) NR13C(R11)2NR13R14;
xe2x80x94C(xe2x95x90O) NR13C(R11)2NR13CO2R13;
xe2x80x94C(xe2x95x90O)NR13xe2x80x94(C1-C4 alkyl)xe2x80x94NR13CO2R13; or
xe2x80x94C(xe2x95x90O)C(R11)2NR13R14;
xe2x80x94C(xe2x95x90O)C(R11)2NR13CO2R13; xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13R14;
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13CO2R13; or
C1-C4 alkoxy substituted with 0-3 groups selected from: R11, C3-C6 cycloalkyl, xe2x80x94CO2R13, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94NR13R14 or OH;
C1-C4 alkyl substituted with 0-3 groups selected from: R11, xe2x95x90NR14, xe2x95x90NNR13C(xe2x95x90O)NR13R14 or xe2x80x94NR13R14;
C2-C4 alkenyl substituted with 0-3 R11;
C2-C4 alkynyl substituted with 0-3 R11;
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 R12;
or R32 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or xe2x80x94NR13R14; or, when R32 is attached to a saturated carbon atom, it may be xe2x95x90O or xe2x95x90S; or when R12 is attached to sulfur it may be xe2x95x90O.
R32, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, xe2x80x94CO2H, xe2x80x94C(R14)xe2x95x90N(OR14);
R34 is selected from:
hydrogen;
C1-C2 alkyl substituted with 0-1 R11 
C1-C2 alkoxy substituted with 0-1 R11 
R35 is selected from:
hydrogen
C1-C2 alkyl substituted with 0-1 R11 
C1-C2 alkoxy substituted with 0-1 R11 
R34 and R35 can be taken together to form a ketal ring, a 3- to 8-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms independently selected from the group O, N, or S;
R36 is selected from:
C1-C2 alkyl substituted with 0-3 R11;
COR37;
NR38R39;
CN;
R37 is selected from:
hydrogen;
C1-C2 alkyl substituted with 0-1 R11;
hydroxyl;
C1-C2 alkoxy substituted with 0-1 R11;
NR38R39;
R38 and R39 are independently selected from:
hydrogen;
C1-C2 alkyl substituted with 0-3 R11; or
an amine protecting group;
provided that:
R4, R4A, R7, and R7A are not all hydrogen;
when W is xe2x80x94OC(xe2x95x90Z)Oxe2x80x94, xe2x80x94C(xe2x95x90Z)xe2x80x94, xe2x80x94P(xe2x95x90O)(R24a)xe2x80x94, xe2x80x94S(xe2x95x90Zxe2x80x2)xe2x80x94 or xe2x80x94S(xe2x95x90Zxe2x80x2)2xe2x80x94, R4 and R7 are not hydrogen;
when R4 and R4A are hydrogen, at least one of the following is not hydrogen: R22, R25, and R26.
[10] Further preferred compounds of the invention of formula (I) are compounds of formula (II): 
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
R4 and R7 are independently selected from the following groups:
hydrogen;
C1-C4 alkyl substituted with 0-3 R11;
C3-C4 alkenyl substituted with 0-3 R11;
R5 is xe2x80x94OR20;
R6 is hydrogen or xe2x80x94OR21;
R20 and R21 are independently hydrogen or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl;
R11 is selected from one or more of the following:
H, keto, halogen, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, xe2x80x94OR13, C2-C4 alkoxyalkyl, C2-C4 alkenyl, ;
C3-C10 cycloalkyl substituted with 0-2 R12;
C1-C4 alkyl substituted with 0-2 R12;
aryl(C1-C3 alkyl)-, substituted with 0-2 R12;
aryl substituted with 0-3 R12; or
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R12;
R12, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1-C4 alkyl, C7-C10 arylalkyl, C1-C4 alkoxy, 2-(1-morpholino)ethoxy, xe2x80x94CO2H, hydroxamic acid, hydrazide, xe2x80x94C(R14)xe2x95x90N(OR14), cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, xe2x80x94OR13, C1-C4 alkyl substituted with xe2x80x94NR13R14, xe2x80x94NR13R14, methylenedioxy, C1-C4 haloalkyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, hydroxymethyl; or
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
R12, when a substituent on nitrogen, is selected from benzyl or methyl;
R13 is H, C1-C4 alkyl, C3-C6 alkoxyalkyl, C2-C4 alkenyl, or benzyl;
R14 is OH, H, CF3, C1-C4 alkyl, C1-C4 alkoxy, NH2, C2-C4 alkenyl, or benzyl;
R13 and R14 can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(R15)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94;
W is selected from:
xe2x80x94N(R22)C(xe2x95x90Z)N(R23)xe2x80x94;
xe2x80x94N(R22)C(xe2x95x90Z)Oxe2x80x94;
xe2x80x94C(R25)(R26)C(xe2x95x90Z)C(R27)(R28)xe2x80x94;
xe2x80x94N(R22)C(xe2x95x90Z)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)C(xe2x95x90Z)Oxe2x80x94;
xe2x80x94N(R22)C(xe2x95x90O)C(xe2x95x90O)N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)C(xe2x95x90Z)Sxe2x80x94;
xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)N(R23)xe2x80x94;
xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)2N(R23)xe2x80x94;
xe2x80x94N(R22)P(xe2x95x90O)(R24a)(N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)2C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)C(R27)(R28)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)2N(R23)xe2x80x94;
xe2x80x94C(R25)C(F2)C(xe2x95x90O)N(R23)xe2x80x94;
xe2x80x94C(R25)C(F2)S(xe2x95x90O)2N(R23)xe2x80x94;
xe2x80x94C(xe2x95x90Z)xe2x80x94;
xe2x80x94P(xe2x95x90O)(R24a)xe2x80x94;
xe2x80x94S(xe2x95x90Zxe2x80x2)xe2x80x94;
xe2x80x94S(xe2x95x90Zxe2x80x2)2xe2x80x94;
wherein:
Z is O, S, or Nxe2x80x94CN;
Zxe2x80x2 is O;
R22 and R23 are independently selected from the following:
hydrogen;
C1-C8 alkyl substituted with 0-3 R31;
C2-C6 alkenyl substituted with 0-3 R31;
C2-C4 alkynyl substituted with 0-3 R31;
R24a is selected from xe2x80x94OH, C1-C4 alkoxy, mono- or di-(C1-C6 alkyl)amino;
R25 and R27 are independently selected from the following:
hydrogen;
C1-C4 alkyl substituted with 0-3 R31;
C2-C4 alkenyl substituted with 0-3 R31;
R26 and R28 are hydrogen or halogen;
R31 is selected from one or more of the following:
keto, halogen, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, xe2x80x94OR13, C2-C4 alkoxyalkyl-, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, xe2x80x94C(R14)xe2x95x90N(OR14), xe2x80x94CO2R13, xe2x80x94S(O)mR13;
aryl substituted with 0-5 R32; or
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R32;
R32, when a substituent on carbon, is selected from one or more of the following:
phenethyl, phenoxy, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, hydrazide, oxime, boronic acid, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 alkylcarbonyloxy, xe2x80x94NHSO2R14, benzyloxy, halogen, 2-(1-morpholino)ethoxy, xe2x80x94CO2R13, hydroxamic acid, xe2x80x94CONR13NR13R14, cyano, sulfonamide, xe2x80x94CHO, C3-C6 cycloalkoxy, xe2x80x94NR13R14, xe2x80x94C(R14)xe2x95x90N(OR14), xe2x80x94NO2, xe2x80x94OR13, xe2x80x94NR4OR41, xe2x80x94SOmR13, xe2x80x94SOmNR13R14, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94OC(xe2x95x90O)NR13R14, xe2x80x94C(xe2x95x90O)R11, xe2x80x94OC(xe2x95x90O)R11, xe2x80x94OCO2R13, phenyl, xe2x80x94C(xe2x95x90O)NR13xe2x80x94(C1-C4 alkyl)xe2x80x94NR13R14, xe2x80x94C(xe2x95x90O)NR40R41, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, or
xe2x80x94C(xe2x95x90O)C(R11)2NR13R14; xe2x80x94C(xe2x95x90O)C(R11)2NR13CO2R13;
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13R14;
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13CO2R13; or
C1-C4 alkoxy substituted with 0-3 groups selected from: R11, C3-C6 cycloalkyl, xe2x80x94CO2R13, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94NR13R14 or OH;
C1-C4 alkyl substituted with 0-3 groups selected from: R11, xe2x95x90NR14, xe2x95x90NNR13C(xe2x95x90O)NR13R14 or xe2x80x94NR13R14;
C2-C4 alkenyl substituted with 0-3 R11;
C2-C4 alkynyl substituted with 0-3 R11;
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-3 R12;
R32, when a substituent on nitrogen, is selected from benzyl or methyl;
R34 is selected from:
hydrogen;
C1-C2 alkyl;
C1-C2 alkoxy;
R35 is selected from:
hydrogen;
C1-C2 alkyl;
C1-C2 alkoxy;
R34 and R35 can be taken together to form a ketal ring, a 3- to 8-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing 1-2 heteroatoms independently selected from the group O, N, or S;
R36 is selected from: C1-C2 alkyl; COR37; NR38R39; CN; CCl3;
R37 is selected from:
hydrogen; C1-C2 alkyl substituted with 0-1 R11;
hydroxyl; C1-C2 alkoxy substituted with 0-1 R11;
NR38R39;
R38 and R39 are independently selected from:
hydrogen; C1-C2 alkyl substituted with 0-3 R11; or
an amine protecting group;
provided that:
R4 and R7 are not both hydrogen;
when W is xe2x80x94C(xe2x95x90Z)xe2x80x94, xe2x80x94P(xe2x95x90O)(R24a)xe2x80x94, xe2x80x94S(xe2x95x90Zxe2x80x2)xe2x80x94 or xe2x80x94S(xe2x95x90Zxe2x80x2)2xe2x80x94, R4 and R7 are not hydrogen;
when R4 is hydrogen, at least one of the following is not hydrogen: R22, R25, R26 and R28.
[11] Preferred compounds of the present invention include compounds of formula (II) described above, wherein:
R4 and R7 are independently selected from the following groups:
hydrogen;
C1-C3 alkyl substituted with 0-1 R11;
R20 and R21 are independently hydrogen or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl;
R11 is selected from one or more of the following:
H; halogen; xe2x80x94OR13;
C3-C10 cycloalkyl substituted with 0-2 R12;
C1-C4 alkyl substituted with 0-2 R12;
aryl (C1-C3 alkyl)-, substituted with 0-2 R12;
aryl substituted with 0-2 R12; or
a heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring system being substituted with 0-2 R12;
R12, when a substituent on carbon, is selected from one or more of the following:
benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3, 2-(1-morpholino)ethoxy, xe2x80x94CO2H, hydroxamic acid, hydrazide, xe2x80x94C(R14)xe2x95x90N(OR14), cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with xe2x80x94NR13R14, xe2x80x94NR13R14, hydroxy, hydroxymethyl; or
R12, when a substituent on nitrogen, is methyl;
R13 is H, C1-C4 alkyl, C2-C4 alkenyl, or benzyl;
R14 is OH, H, CF3, C1-C4 alkyl, C1-C4 alkoxy, NH2, C2-C4 alkenyl, or benzyl;
R13 and R14 can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(R15)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94;
W is selected from:
xe2x80x94N(R22)C(xe2x95x90Z)N(R23)xe2x80x94;
xe2x80x94N(R22)C(xe2x95x90Z)Oxe2x80x94;
xe2x80x94C(R25)(R26)C(xe2x95x90Z)C(R27)(R28)xe2x80x94;
xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)N(R23)xe2x80x94;
xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)2N(R23)xe2x80x94;
xe2x80x94C(R25)(R26)C(R34)(R35)C(R27)(R28)xe2x80x94;
xe2x80x94Nxe2x95x90C(R36)N(R23)xe2x80x94;
xe2x80x94C(xe2x95x90Z)xe2x80x94;
Z is O, S, or Nxe2x80x94CN;
Zxe2x80x2 is O;
R22 and R23 are independently selected from the following:
hydrogen;
C1-C8 alkyl substituted with 0-3 R31;
C2-C6 alkenyl substituted with 0-3 R31;
C2-C4 alkynyl substituted with 0-3 R31;
R25 and R27 are independently selected from the following:
hydrogen;
C1-C4 alkyl substituted with 0-3 R31;
C3-C4 alkenyl substituted with 0-3 R31;
R26 and R28 are hydrogen or halogen;
R31 is selected from one or more of the following:
halogen, xe2x80x94OR13, C1-C4 alkyl, C3-C10 cycloalkyl, xe2x80x94C(R14)xe2x95x90N(OR14), xe2x80x94CO2R13, xe2x80x94S(O)mR13;
aryl substituted with 0-5 R32; or
a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring being substituted with 0-2 R32;
R32, when a substituent on carbon, is selected from one or more of the following:
benzyloxy, halogen, 2-(1-morpholino)ethoxy, xe2x80x94CO2R13, hydroxamic acid, xe2x80x94CONR13NR13R14, cyano, boronic acid, xe2x80x94CHO, C3-C6 cycloalkoxy, xe2x80x94NR13R14, xe2x80x94C(R14)xe2x95x90N(OR14), NO2, xe2x80x94OR13, xe2x80x94NR40R41, xe2x80x94SOmR13, xe2x80x94SOmNR13R14, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94OC(xe2x95x90O)NR13R14, xe2x80x94C(xe2x95x90O)R11, xe2x80x94OC(xe2x95x90O)R11, xe2x80x94OCO2R13, phenyl, xe2x80x94C(xe2x95x90O)NR13xe2x80x94(C1-C4 alkyl)xe2x80x94NR13R14, xe2x80x94C(xe2x95x90O)NR40R41, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl,
xe2x80x94C(xe2x95x90O)C(R11)2NR13R14;
xe2x80x94C(xe2x95x90O)C(R11)2NR13CO2R13; xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13R14;
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13CO2R13; or
C1-C4 alkoxy substituted with 0-3 groups selected from: R11, C3-C6 cycloalkyl, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94NR13R14 or OH;
C1-C4 alkyl substituted with 0-3 groups selected from: R11, xe2x95x90NR14, xe2x95x90NNR13C(xe2x95x90O)NR13R14 or xe2x80x94NR13R14;
C2-C4 alkenyl substituted with 0-3 R11;
C2-C4 alkynyl substituted with 0-3 R11;
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 R12;
R32, when a substituent on nitrogen, is methyl;
R34 is selected from:
hydrogen;
C1-C2 alkyl;
C1-C2 alkoxy;
R35 is selected from:
hydrogen;
C1-C2 alkyl;
C1-C2 alkoxy;
R36 is selected from: C1-C2 alkyl; COR37; NR38R39; CN; CCl3;
R37 is selected from:
hydrogen;
C1-C2 alkyl substituted with 0-1 R11;
hydroxyl;
C1-C2 alkoxy substituted with 0-1 R11;
xe2x80x94NR38R39;
R38 and R39 are independently selected from:
hydrogen;
C1-C2 alkyl substituted with 0-3 R11; or
an amine protecting group;
provided that:
R4 and R7 are not both hydrogen;
when W is xe2x80x94C(xe2x95x90Z)xe2x80x94, R4 and R7 are not hydrogen;
when R4 is hydrogen, at least one of the following is not hydrogen: R22, R25, R26 and R28.
[12] Preferred compounds of the present invention are compounds of formula (II) described above, wherein:
R4 and R7 are selected from benzyl, fluorobenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl, thienylmethyl, hydroxybenzyl, pyridylmethyl, naphthylmethyl;
R5 is xe2x80x94OH;
R6 is hydrogen or xe2x80x94OH;
R13 is H, C1-C4 alkyl, C2-C4 alkenyl, or benzyl;
R14 is OH, H, CF3, C1-C4 alkyl, C1-C4 alkoxy, NH2, C2-C4 alkenyl, or benzyl;
R13 and R14 can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(R15)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94;
W is selected from:
xe2x80x94N(R22)C(xe2x95x90O)N(R23)xe2x80x94;
xe2x80x94N(R22)C(xe2x95x90Nxe2x80x94CN)N(R23)xe2x80x94;
xe2x80x94N(R22)S(xe2x95x90O)2N(R23)xe2x80x94;
xe2x80x94C(xe2x95x90O)xe2x80x94;
xe2x80x94N(R22)C(xe2x95x90S)N(R23)xe2x80x94; or
xe2x80x94C(xe2x95x90Nxe2x80x94CN)xe2x80x94;
R22 and R23 are independently selected from the following:
hydrogen;
C1-C8 alkyl substituted with 0-2 R31;
C2-C6 alkenyl substituted with 0-2 R31;
C2-C4 alkynyl substituted with 0-2 R31;
R31 is selected from one or more of the following:
halogen, xe2x80x94OR13, C1-C4 alkyl, C3-C10 cycloalkyl, xe2x80x94C(R14)xe2x95x90N(OR14), xe2x80x94CO2R13, xe2x80x94S(O)mR13;
aryl substituted with 0-5 R32; or
a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, benzimidazolyl, benzotriazolyl, indazolyl, benzoxazolinyl, benzoxazolyl, said heterocyclic ring being substituted with 0-2 R32;
R32, when a substituent on carbon, is selected from one or more of the following:
xe2x80x94CONH2, xe2x80x94CO2H, xe2x80x94CHO, xe2x80x94CH2NHOH, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, hydroxy, hydroxymethyl, xe2x80x94C(R14)xe2x95x90N(OR14), halogen, methoxy, methyl, nitro, cyano, allyloxy, xe2x80x94CO2CH3, xe2x80x94NHCHO, xe2x80x94NHCOCH3, xe2x80x94OCO2CH3, xe2x80x94CHxe2x95x90NCH2CH2OH, xe2x80x94OCONHCH2C6H5, xe2x80x94OCONHCH3, oxazolidinyl, xe2x80x94Cxe2x95x90Cxe2x80x94CH2OH, xe2x80x94COCH3, hydroxyethyl, C1-C3 alkyl (said alkyl substituted with 0-4 halogen, or OH), tetrazolyl, xe2x80x94OCH2CONH2, xe2x80x94CONHNH2, xe2x80x94CHxe2x95x90NNHCONH2, xe2x80x94CONHOCH3, xe2x80x94CH2CH(OH)CH2OH, adamantamido, hydroxyethoxy, dihydroxyethyl, xe2x80x94C(NH2)xe2x95x90NH, xe2x80x94CONHCH3, xe2x80x94B(OH)2, benzyloxy, xe2x80x94CONHCH2CH3, xe2x80x94CON(CH2CH3)2, methylthio, xe2x80x94SO2CH3, xe2x80x94NHCONH2, xe2x80x94NHCONHCH3, xe2x80x94NHCOCH2N(CH3)2, xe2x80x94NHCOCH2NHCH3, xe2x80x94NHCOCH2NHCO2CH2C6H5, xe2x80x94NHCOCH2NH2, xe2x80x94NHCOCH(CH3)NHCO2CH2C6H5, xe2x80x94NHCOCH(CH2C6H5)NHCO2CH2C6H5, xe2x80x94NHCOCH(CH3)NH2, xe2x80x94NHCOCH(CH2C6H5)NH2, xe2x80x94CO2CH2CH3, xe2x80x94CONHCH2CH2CH3, xe2x80x94CONHCH(CH3)2, xe2x80x94CH2-imidazole, xe2x80x94COC(CH3)3, xe2x80x94CH(OH)CF3, xe2x80x94CO-imidazole, xe2x80x94CO-pyrazolyl, oxadiazolidinonyl, xe2x80x94COCF3, xe2x80x94COCH2CH3, xe2x80x94COCH2CH2CH3, pyrazolyl, xe2x80x94SO2NH2, xe2x80x94C(CH2CH3)xe2x95x90N(OH) or xe2x80x94C(CF3)xe2x95x90N(OH), phenyl, acetoxy, hydroxyamino, xe2x80x94N(CH3)(CHO), cyclopropylmethoxy, xe2x80x94CONR13R14, xe2x80x94CONHOH, (diethylaminoethyl)aminocarbonyl, (N-ethyl,N-methylaminoethyl)aminocarbonyl, (4-methylpiperazinylethyl)aminocarbonyl, pyrrolidinylethyl)aminocarbonyl, (piperidinylethyl)aminocarbonyl, xe2x80x94NHCOCH2NHCH3, N-(2-(4-morpholino)ethyl)aminocarbonyl, N-(2-(N,N-dimethylamino)ethyl)aminocarbonyl;
R32, when a substituent on nitrogen, is methyl.
[13] Also preferred are compounds of the formula: 
wherein:
Z is ), S, or Nxe2x80x94CN;
R4 and R7 are independently selected from: benzyl, fluorobenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl, thienylmethyl, hydroxybenzyl, pyridylmethyl, naphthylmethyl;
R22 and R23 are independently selected from the group consisting of:
hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CHxe2x95x90C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(xe2x95x90O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2Nxe2x95x90CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(xe2x95x90NOH))-benzyl, (H2NNHC(xe2x95x90O))-benzyl, (H2NC(xe2x95x90O)NHNxe2x95x90CH)-benzyl, (CH3ONHC(xe2x95x90O))-benzyl, (HONHC(xe2x95x90O))-benzyl, (CH3NHC(xe2x95x90O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)benzyl, hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(xe2x95x90O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N, N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(xe2x95x90O))-benzyl, (pyrazolyl-C(xe2x95x90O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(xe2x95x90O)NH)-benzyl, (H2NC(xe2x95x90O)NH)-benzyl, (HC(xe2x95x90O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(xe2x95x90NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(xe2x95x90NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzylxe2x80x94NHC(xe2x95x90O)O)benzyl, (CH3NHC(xe2x95x90O)O)benzyl, (NH2C(xe2x95x90O)CH2O)benzyl, (NH2C(xe2x95x90NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3Cxe2x80x94C(xe2x95x90O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(xe2x95x90NOH))benzyl, (H2NC(xe2x95x90NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl.
[14] Also preferred are compounds of formula (IIa): 
wherein R22 and R23 are independently selected from the group consisting of:
hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CHxe2x95x90C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(xe2x95x90O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2Nxe2x95x90CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(xe2x95x90NOH))-benzyl, (H2NNHC(xe2x95x90O))-benzyl, (H2NC(xe2x95x90O)NHNxe2x95x90CH)-benzyl, (CH3ONHC(xe2x95x90O))-benzyl, (HONHC(xe2x95x90O))-benzyl, (CH3NHC(xe2x95x90O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)-benzyl, hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(xe2x95x90O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(xe2x95x90O))-benzyl, (pyrazolyl-C(xe2x95x90O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(xe2x95x90O)NH)-benzyl, (H2NC(xe2x95x90O)NH)-benzyl, (HC(xe2x95x90O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(xe2x95x90NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(xe2x95x90NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(xe2x95x90O)O)benzyl, (CH3NHC(xe2x95x90O)O)benzyl, (NH2C(xe2x95x90O)CH2O)benzyl, (NH2C(xe2x95x90NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3Cxe2x80x94C(xe2x95x90O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(xe2x95x90NOH))benzyl, (H2NC(xe2x95x90NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl.
[15] Specifically preferred are compounds of formula (IIa): 
selected from the group consisting of:
the compound of formula (IIa) wherein R22 is allyl and R23 is allyl;
the compound of formula (IIa) wherein R22 is propyl and R23 is propyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is cyclopropylmethyl;
the compound of formula (IIa) wherein R22 is n-hexyl and R23 is n-hexyl;
the compound of formula (IIa) wherein R22 is n-butyl and R23 is n-butyl;
the compound of formula (IIa) wherein R22 is CH2CHxe2x95x90C(CH3)2 and R23 is CH2CHxe2x95x90C(CH3)2;
the compound of formula (IIa) wherein R22 is CH2CHxe2x95x90C(CH3)2 and R23 is H;
the compound of formula (IIa) wherein R22 is i-pentyl and R23 is i-pentyl;
the compound of formula (IIa) wherein R22 is 2-methallyl and R23 is 2-methallyl;
the compound of formula (IIa) wherein R22 is n-pentyl and R23 is n-pentyl;
the compound of formula (IIa) wherein R22 is benzyl and R23 is benzyl;
the compound of formula (IIa) wherein R22 is i-hexyl and R23 is i-hexyl;
the compound of formula (IIa) wherein R22 is allyl and R23 is isoprenyl;
the compound of formula (IIa) wherein R22 is 1-cinnamyl and R23 is 1-cinnamyl;
the compound of formula (IIa) wherein R22 is 4-fluorobenzyl and R23 is 4-fluorobenzyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is benzyl;
the compound of formula (IIa) wherein R22 is allyl and R23 is benzyl;
the compound of formula (IIa) wherein R22 is CH2CHxe2x95x90C(CH3)2 and R23 is cyclopropylmethyl;
the compound of formula (IIa) wherein R22 is 2-naphthylmethyl and R23 is 2-napthylmethyl;
the compound of formula (IIa) wherein R22 is n-butyl and R23 is benzyl;
the compound of formula (IIa) wherein R22 is allyl and R23 is cyclopropylmethyl;
the compound of formula (IIa) wherein R22 is n-butyl and R23 is cyclopropylmethyl;
the compound of formula (IIa) wherein R22 is CH2CHxe2x95x90C(CH3)2 and R23 is benzyl;
the compound of formula (IIa) wherein R22 is benzyl and R23 is ethyl;
the compound of formula (IIa) wherein R22 is benzyl and R23 is 4-pyridinylmethyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 4-pyridinylmethyl;
the compound of formula (IIa) wherein R22 is benzyl and R23 is cyclopentylmethyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is cyclopentylmethyl;
the compound of formula (IIa) wherein R22 is benzyl and R23 is n-propyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is cinnamyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is cyclopentylmethyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is benzyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 2-pyridinylmethyl;
the compound of formula (IIa) wherein R22 is 3-cyanobenzyl and R23 is 3-cyanobenzyl;
the compound of formula (IIa) wherein R22 is allyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is n-propyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is n-butyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is hydrogen and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is 4-pyridinylmethyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is allyl and R23 is cyclopentylmethyl;
the compound of formula (IIa) wherein R22 is allyl and R23 is 2-quinolinylmethyl;
the compound of formula (IIa) wherein R22 is 3-pyridinylmethyl and R23 is cyclopropylmethyl;
the compound of formula (IIa) wherein R22 is 3-pyridinylmethyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is 3-hydroxybenzyl and R23 is 3-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is vinylbenzyl and R23 is vinylbenzyl;
the compound of formula (IIa) wherein R22 is 3-allyloxybenzyl and R23 is 3-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is 3-pyridinylmethyl and R23 is 3-pyridinylmethyl;
the compound of formula (IIa) wherein R22 is 2-naphthylmethyl and R23 is 4-fluorobenzyl;
the compound of formula (IIa) wherein R22 is 4-hydroxybenzyl and R23 is 4-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is 3-hydroxymethylbenzyl and R23 is 3-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-carbomethoxybenzyl and R23 is 3-carbomethoxybenzyl;
the compound of formula (IIa) wherein R22 is 4-hydroxymethylbenzyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-formylbenzyl and R23 is 3-formylbenzyl;
the compound of formula (IIa) wherein R22 is 4-cyanobenzyl and R23 is 4-cyanobenzyl;
the compound of formula (IIa) wherein R22 is 4-formylbenzyl and R23 is 4-formylbenzyl;
the compound of formula (IIa) wherein R22 is 4-hydroxybenzyl and R23 is 2-propyl;
the compound of formula (IIa) wherein R22 is 3-hydroxybenzyl and R23 is 2-propyl;
the compound of formula (IIa) wherein R22 is 3-carboxybenzyl and R23 is 3-carboxybenzyl;
the compound of formula (IIa) wherein R22 is 3-formaldoximebenzyl and R23 is 3-formaldoximebenzyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 3-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 4-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is cyclobutylmethyl and R23 is cyclobutylmethyl;
the compound of formula (IIa) wherein R22 is cyclopentylmethyl and R23 is cyclopentylmethyl;
the compound of formula (IIa) wherein R22 is n-butyl and R23 is CH2CHxe2x95x90C(CH3)2;
the compound of formula (IIa) wherein R22 is n-butyl and R23 is cyclopentylmethyl;
the compound of formula (IIa) wherein R22 is benzyl and R23 is H;
the compound of formula (IIa) wherein R22 is 3-fluorobenzyl and R23 is 3-fluorobenzyl;
the compound of formula (IIa) wherein R22 is 3-methoxybenzyl and R23 is 3-methoxybenzyl;
the compound of formula (IIa) wherein R22 is 3,4-difluorobenzyl and R23 is 3,4-difluorobenzyl;
the compound of formula (IIa) wherein R22 is 4-methylbenzyl and R23 is 4-methylbenzyl;
the compound of formula (IIa) wherein R22 is 4-chlorobenzyl and R23 is 4-chlorobenzyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 4-fluorobenzyl;
the compound of formula (IIa) wherein R22 is 3-chlorobenzyl and R23 is 3-chlorobenzyl;
the compound of formula (IIa) wherein R22 is 3-nitrobenzyl and R23 is 3-nitrobenzyl;
the compound of formula (IIa) wherein R22 is 3-methylbenzyl and R23 is 3-methylbenzyl;
the compound of formula (IIa) wherein R22 is 3-bromobenzyl and R23 is 3-bromobenzyl;
the compound of formula (IIa) wherein R22 is 4-fluorobenzyl and R23 is H;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 3-chlorobenzyl;
the compound of formula (IIa) wherein R22 is 3-aminobenzyl and R23 is 3-aminobenzyl;
the compound of formula (IIa) wherein R22 is 4-aminobenzyl and R23 is 4-aminobenzyl;
the compound of formula (IIa) wherein R22 is 3-nitrobenzyl and R23 is H;
the compound of formula (IIa) wherein R22 is 3-(NHCHO)benzyl and R23 is 3-(NHCHO)benzyl;
the compound of formula (IIa) wherein R22 is 3-(NHCOCH3)benzyl and R23 is 3-(NHCOCH3)benzyl;
the compound of formula (IIa) wherein R22 is 3,4-dihydroxybenzyl and R23 is 3,4-dihydroxybenzyl;
the compound of formula (IIa) wherein R22 is 3-formaldoximebenzyl and R23 is 3-(N-hydroxy)aminomethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-(N-hydroxy)aminomethylbenzyl and R23 is 3-(N-hydroxy)aminomethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-(CH3O(xe2x95x90O)Oxe2x80x94)benzyl and R23 is 3-(CH3O(xe2x95x90O)Oxe2x80x94)benzyl;
the compound of formula (IIa) wherein R22 is 3-(1-hydroxyethyl)benzyl and R23 is 3-(1-hydroxyethyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(HOCH2CH2Nxe2x95x90CH)benzyl and R23 is 3-(HOCH2CH2Nxe2x95x90CH)benzyl;
the compound of formula (IIa) wherein R22 is 3-(HOCH2CH2Nxe2x95x90CH)benzyl and R23 is 3-(2-oxazolidinyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(C6H5CH2NHC(xe2x95x90O)O)benzyl and R23 is 3-(C6H5CH2NHC(xe2x95x90O)O)benzyl;
the compound of formula (IIa) wherein R22 is 3-(CH3NHC(xe2x95x90O)O)benzyl and R23 is 3-(CH3NHC(xe2x95x90O)O)benzyl;
the compound of formula (IIa) wherein R22 is 3-(HOCH2CC)benzyl and R23 is 3-bromobenzyl;
the compound of formula (IIa) wherein R22 is 3-acetylbenzyl and R23 is 3-bromobenzyl;
the compound of formula (IIa) wherein R22 is 3-acetylbenzyl and R23 is 3-acetylbenzyl;
the compound of formula (IIa) wherein R22 is 3-(CH3C(xe2x95x90NOH))benzyl and R23 is 3-(CH3C(xe2x95x90NOH))benzyl;
the compound of formula (IIa) wherein R22 is 3-(1-hydroxyethyl)benzyl and R23 is 3-bromobenzyl;
the compound of formula (IIa) wherein R22 is 3-(chloromethyl)benzyl and R23 is 3-(chloromethyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(5-tetrazolyl)benzyl and R23 is cyclopropylmethyl;
the compound of formula (IIa) wherein R22 is 3-cyanobenzyl and R23 is 3-formylbenzyl;
the compound of formula (IIa) wherein R22 is 4-acetoxybenzyl and R23 is 4-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is 3-aminocarbonylbenzyl and R23 is 3-aminocarbonylbenzyl;
the compound of formula (IIa) wherein R22 is 3-(H2NCOCH2O)benzyl and R23 is 3-(H2NCOCH2O)benzyl;
the compound of formula (IIa) wherein R22 is 3-hydroxybenzyl and R23 is H;
the compound of formula (IIa) wherein R22 is 3-methylbenzyl and R23 is 3-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is 2-naphthylmethyl and R23 is 3-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is 3-(H2NNHC(xe2x95x90O))-benzyl and R23 is 3-(H2NNHC(xe2x95x90O))-benzyl;
the compound of formula (IIa) wherein R22 is 4-(H2NNHC(xe2x95x90O))-benzyl and R23 is 4-(H2NNHC(xe2x95x90O))-benzyl;
the compound of formula (IIa) wherein R22 is 4-hydroxymethylbenzyl and R23 is 3-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is 3-(H2NC(xe2x95x90O)NHNxe2x95x90CH)-benzyl and R23 is 3-(H2NC(xe2x95x90O)NHNxe2x95x90CH)-benzyl;
the compound of formula (IIa) wherein R22 is 3-[(N-methoxy)aminocarbonyl]-benzyl and R23 is 3-[(N-methoxy)aminocarbonyl]-benzyl;
the compound of formula (IIa) wherein R22 is 4-[(N-methoxy)aminocarbonyl]-benzyl and R23 is 4-[(N-methoxy)aminocarbonyl]-benzyl;
the compound of formula (IIa) wherein R22 is 3-(HOCH2CH(OH)CH2O)benzyl and R23 is 3-(HOCH2CH(OH)CH2O)benzyl;
the compound of formula (IIa) wherein R22 is 3-(2-hydroxyethoxy)benzyl and R23 is 3-(2-hydroxyethoxy)benzyl;
the compound of formula (IIa) wherein R22 is 3-(1,2-dihydroxyethyl)benzyl and R23 is 4-(1,2-dihydroxyethyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-aminocarbonylbenzyl and R23 is 3-(H2NC(xe2x95x90NH))benzyl;
the compound of formula (IIa) wherein R22 is 4-hydroxybenzyl and R23 is 3-formyl-4-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is 3-carbomethoxybenzyl and R23 is 3-(N-methylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(N-methylaminocarbonyl)benzyl and R23 is 3-(N-methylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is benzyl and R23 is 3-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is 2-naphthylmethyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-(1,2-dihydroxyethyl)benzyl and R23 is 3-(1,2-dihydroxyethyl)benzyl;
the compound of formula (IIa) wherein R22 is 4-(1,2-dihydroxyethyl)benzyl and R23 is 4-(1,2-dihydroxyethyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-hydroxymethylbenzyl and R23 is 3-(N-methylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 4-hydroxymethylbenzyl and R23 is hydrogen;
the compound of formula (IIa) wherein R22 is 3-(boronic acid)benzyl and R23 is 3-(boronic acid)benzyl;
the compound of formula (IIa) wherein R22 is 3-nitrobenzyl and R23 is 3-benzyloxybenzyl;
the compound of formula (IIa) wherein R22 is 3-aminobenzyl and R23 is 3-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is 3-(N-ethylaminocarbonyl)benzyl and R23 is 3-(N-ethylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-carbomethoxybenzyl and R23 is 3-(N,N-diethylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-carbomethoxybenzyl and R23 is 3-(N-ethylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 6-hydroxy-1-hexyl and R23 is hydrogen;
the compound of formula (IIa) wherein R22 is 6-hydroxy-1-hexyl and R23 is 6-hydroxy-1-hexyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 6-hydroxy-1-hexyl;
the compound of formula (IIa) wherein R22 is 5-carboxy-1-pentyl and R23 is 5-carboxy-1-pentyl;
the compound of formula (IIa) wherein R22 is 3-iodobenzyl and R23 is 3-iodobenzyl;
the compound of formula (IIa) wherein R22 is benzyl and R23 is 2-(hydroxymethyl)-cyclopropylmethyl;
the compound of formula (IIa) wherein R22 is 3-(thiomethyl)benzyl and R23 is 3-(thiomethyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(methylsulfonyl)benzyl and R23 is 3-(methylsulfonyl)benzyl;
the compound of formula (IIa) wherein R22 is 6-hexenyl and R23 is 6-hexenyl;
the compound of formula (IIa) wherein R22 is 6-bromo-5-hydroxy-1-hexyl and R23 is 6-bromo-5-hydroxy-1-hexyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is 5-hydroxy-1-pentyl;
the compound of formula (IIa) wherein R22 is 3-aminobenzyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-(H2NC(xe2x95x90O)NH)benzyl and R23 is 3-(H2NC(xe2x95x90O)NH)benzyl;
the compound of formula (IIa) wherein R22 is 3-(N-methylamino)benzyl and R23 is 3-(N-methylamino)benzyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 3-aminobenzyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 3-nitrobenzyl;
the compound of formula (IIa) wherein R22 is 3-(N,N-dimethylamino)benzyl and R23 is 3-(N,N-dimethylamino)benzyl;
the compound of formula (IIa) wherein R22 is 3-nitrobenzyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-aminobenzyl and R23 is 3-(CH3NHC(xe2x95x90O)NH)benzyl;
the compound of formula (IIa) wherein R22 is 3-(CH3NHC(xe2x95x90O)NH)benzyl and R23 is 3-(CH3NHC(xe2x95x90O)NH)benzyl;
the compound of formula (IIa) wherein R22 is 3-(N-methylamino)benzyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-((N,N-dimethylaminoglycyl)amino)benzyl and R23 is 3-((N,N-dimethylaminoglycyl)amino)benzyl;
the compound of formula (IIa) wherein R22 is 3-((N-methylaminoglycyl)amino)benzyl and R23 is 3-((N-methylaminoglycyl)amino)benzyl;
the compound of formula (IIa) wherein R22 is 3-((N,N-dimethylaminoglycyl)amino)benzyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-((N-phenylmethoxycarbonylaminoglycyl)amino)benzyl and R23 is 3-((N-phenylmethoxycarbonylaminoglycyl)amino)benzyl;
the compound of formula (IIa) wherein R22 is 3-(glycylamino)benzyl and R23 is 3-(glycylamino)benzyl;
the compound of formula (IIa) wherein R22 is 3-(glycylamino)benzyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-((N-phenylmethoxycarbonylamino-L-alanyl)amino)benzyl and R23 is 3-((N-phenylmethoxycarbonylamino-L-alanyl)amino)benzyl;
the compound of formula (IIa) wherein R22 is 3-((N-phenylmethoxycarbonylamino-L-phenylalanyl)amino)benzyl and R23 is 3-((N-phenylmethoxycarbonylamino-L-phenylalanyl)amino)benzyl;
the compound of formula (IIa) wherein R22 is 3-(L-alanyl)amino)benzyl and R23 is 3-(L-alanyl)amino)benzyl;
the compound of formula (IIa) wherein R22 is 3-(L-phenylalanyl)amino)benzyl and R23 is 3-(L-phenylalanyl)amino)benzyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is hydrogen;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is benzyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 6-hydroxy-1-hexyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is 3-hydroxybenzyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is (5-methylsulfonyl)-1-pentyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is 5-(CH3S(O))-1-pentyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is cyclopropylmethyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is 5-methoxy-1-pentyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is 3-cyanobenzyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is 3-carboethoxybenzyl;
the compound of formula (IIa) wherein R22 is 4-hydroxy-1-hexyl and R23 is 4-hydroxy-1-hexyl;
the compound of formula (IIa) wherein R22 is 4-hydroxy-1-hexyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is 4-oxime-1-hexyl and R23 is 4-oxime-1-hexyl;
the compound of formula (IIa) wherein R22 is 5-hydroxy-1-pentyl and R23 is 3-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 6-amino-1-hexyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-(N,N-diethylaminocarbonyl)benzyl and R23 is 3-(N,N-diethylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-carbomethoxybenzyl and R23 is 3-(N,N-diethylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-carbomethoxybenzyl and R23 is 3-(N-ethylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-hydroxymethylbenzyl and R23 is hydrogen;
the compound of formula (IIa) wherein R22 is 3-hydroxymethylbenzyl and R23 is 3-(N,N-diethylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-hydroxymethylbenzyl and R23 is 3-(N-ethylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(N-propylaminocarbonyl)benzyl and R23 is 3-(N-propylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(HO2C)benzyl and R23 is 3-(N-isopropylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(HO2C)benzyl and R23 is 3-(N-propylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(HO2C)benzyl and R23 is benzyl;
the compound of formula (IIa) wherein R22 is 3-(HO2C)benzyl and R23 is cyclopropylmethyl;
the compound of formula (IIa) wherein R22 is 4-hydroxymethylbenzyl and R23 is 3-(HO2C)benzyl;
the compound of formula (IIa) wherein R22 is 3-hydroxymethylbenzyl and R23 is 3-pyridinylmethyl;
the compound of formula (IIa) wherein R22 is 4-hydroxymethylbenzyl and R23 is 3-aminocarbonylbenzyl;
the compound of formula (IIa) wherein R22 is 3-aminobenzyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is cyclopropylmethyl and R23 is 3-aminocarbonylbenzyl;
the compound of formula (IIa) wherein R22 is 3-aminocarbonylbenzyl and R23 is hydrogen;
the compound of formula (IIa) wherein R22 is 3-hydroxymethylbenzyl and R23 is 3-(N-ethylaminocarbonyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-hydroxymethylbenzyl and R23 is 3-(N-methylamino)benzyl;
the compound of formula (IIa) wherein R22 is 3-(N-methylamino)benzyl and R23 is 2-naphthylmethyl;
the compound of formula (IIa) wherein R22 is 4-formylbenzyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-(1-hydroxy-1-ethyl)benzyl and R23 is 3-(1-hydroxyethyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-pyridinylmethyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 3-(N-imidazolylmethyl)benzyl and R23 is 3-(N-imidazolylmethyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(2,2-dimethyl-1-propionyl)benzyl and R23 is 3-(2,2-dimethyl-1-propionyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(2,2,2-trifluoro-1-hydroxyethyl)benzyl and R23 is 3-(2,2,2-trifluoro-1-hydroxyethyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(2-imidazolyl-C(xe2x95x90O))benzyl and R23 is 3-(2-imidazolyl-C(xe2x95x90O))benzyl;
the compound of formula (IIa) wherein R22 is 3-(3-hydroxy-1-propyn-1-yl)benzyl and R23 is 3 (3-hydroxy-1-propyn-1-yl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(2,2,2-trifluoroacetyl)benzyl and R23 is 3-(2,2,2-trifluoroacetyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-propionylbenzyl and R23 is 3-propionylbenzyl;
the compound of formula (IIa) wherein R22 is 3-(4-pyrazolyl)benzyl and R23 is 3-(4-pyrazolyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(CH3CH2C(xe2x95x90N-OH))benzyl and R23 is 3-(CH3CH2C(xe2x95x90N-OH))benzyl;
the compound of formula (IIa) wherein R22 is 3-sulfonamidobenzyl and R23 is 3-sulfonamidobenzyl;
the compound of formula (IIa) wherein R22 is 3-(CF3CH2C(xe2x95x90N-OH))benzyl and R23 is 3-(CF3CH2C(xe2x95x90N-OH))benzyl;
the compound of formula (IIa) wherein R22 is 4-fluoromethylbenzyl and R23 is 4-fluoromethylbenzyl;
the compound of formula (IIa) wherein R22 is 4-(1-hydroxyethyl)benzyl and R23 is 4-(1-hydroxyethyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(5-methyl-1,2,3-oxadiazolyl)benzyl and R23 is 3-(5-methyl-1,2,3-oxadiazolyl)benzyl;
the compound of formula (IIa) wherein R22 is 3-(H2NC(xe2x95x90NOH)benzyl and R23 is 3-(H2NC(xe2x95x90NOH)benzyl;
the compound of formula (IIa) wherein R22 is 3-(H2NC(xe2x95x90NOH)-4-fluorobenzyl and R23 is 3-(H2NC(xe2x95x90NOH)-4-fluorobenzyl;
the compound of formula (IIa) wherein R22 is 5-benzotriazolylmethyl and R23 is 5-benzotriazolylmethyl;
the compound of formula (IIa) wherein R22 is 5-benzimidazolylmethyl and R23 is 5-benzimidazolylmethyl;
the compound of formula (IIa) wherein R22 is 5-benzimidazolylmethyl and R23 is 5-benzimidazolylmethyl;
the compound of formula (IIa) wherein R22 is 5-benzotriazolylmethyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IIa) wherein R22 is 5-benzotriazolylmethyl and R23 is 3-(3-pyrazolyl)benzyl;
the compound of formula (IIa) wherein R22 is 5-indazolylmethyl and R23 is 5-indazolylmethyl;
the compound of formula (IIa) wherein R22 is 3-chloro-5-indazolylmethyl and R23 is 3-chloro-5-indazolylmethyl;
the compound of formula (IIa) wherein R22 is 3-methylamino-5-indazolylmethyl and R23 is 3-methylamino-5-indazolylmethyl;
the compound of formula (IIa) wherein R22 is 3-ethylamino-5-indazolylmethyl and R23 is 3-ethylamino-5-indazolylmethyl;
the compound of formula (IIa) wherein R22 is 6-indazolylmethyl and R23 is 6-indazolylmethyl;
the compound of formula (IIa) wherein R22 is 3-amino-5-benzisoxazolylmethyl and R23 is 3-amino-5-benzisoxazolylmethyl;
the compound of formula (IIa) wherein wherein R22 is 5-(2-amino)benzoxazolyl and R23 is 5-(2-amino)benzoxazolyl.
[16] Also preferred are compounds of formula (IIaa): 
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
R4 and R7 are independently selected from: benzyl, fluorobenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl, hydroxybenzyl, thienylmethyl, pyridylmethyl, naphthylmethyl;
R22 and R23 are independently selected from:
hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CHxe2x95x90C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(xe2x95x90O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2Nxe2x95x90CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(xe2x95x90NOH))-benzyl, (H2NNHC(xe2x95x90O))-benzyl, (H2NC(xe2x95x90O)NHNxe2x95x90CH)-benzyl, (CH3ONHC(xe2x95x90O))-benzyl, (HONHC(xe2x95x90O))-benzyl, (CH3NHC(xe2x95x90O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)-benzyl, hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(xe2x95x90O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(xe2x95x90O))-benzyl, (pyrazolyl-C(xe2x95x90O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(xe2x95x90O)NH)-benzyl, (H2NC(xe2x95x90O)NH)-benzyl, (HC(xe2x95x90O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(xe2x95x90NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(xe2x95x90NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(xe2x95x90O)O)benzyl, (CH3NHC(xe2x95x90O)O)benzyl, (NH2C(xe2x95x90O)CH2O)benzyl, (NH2C(xe2x95x90NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3Cxe2x80x94C(xe2x95x90O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(xe2x95x90NOH))benzyl, (H2NC(xe2x95x90NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl.
[17] Specifically preferred are compounds of formula (IIaa): 
selected from the group consisting of:
the compound of formula (IIaa) wherein R4 and R7 are isobutyl, R22 and R23 are cyclopropylmethyl;
the compound of formula (IIaa) wherein R4 and R7 are isobutyl, R22 and R23 are allyl;
the compound of formula (IIaa) wherein R4 is 4-nitrobenzyl, R7 is 2-nitrobenzyl, R22 and R23 are cyclopropylmethyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-nitrobenzyl, R22 and R23 are cyclopropylmethyl;
the compound of formula (IIaa) wherein R4 is 4-nitrobenzyl, R7 is 2-nitrobenzyl, R22 and R23 are n-butyl;
the compound of formula (IIaa) wherein R4 is 4-aminobenzyl, R7 is 2-aminobenzyl, R22 and R23 are cyclopropylmethyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-fluorobenzyl, R22 and R23 are 3-hydroxybenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-fluorobenzyl, R22 and R23 are cyclopropylmethyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-fluorobenzyl, R22 and R23 are 4-hydroxymethylbenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-fluorobenzyl, R22 and R23 are 3-aminocarbonylbenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-fluorobenzyl, R22 and R23 are 3-acetylbenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-fluorobenzyl, R22 and R23 are 3-butyrylbenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-fluorobenzyl, R22 and R23 are 3-hydroxymethylbenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-fluorobenzyl, R22 and R23 are 3-(CH3C(xe2x95x90NOH)benzyl;
the compound of formula (IIaa) wherein R4 and R7 are 3-methoxybenzyl, R22 and R23 are benzyl.
the compound of formula (IIaa) wherein R4 and R7 are 4-fluorobenzyl, R22 and R23 are 3-(H2NC(xe2x95x90NOH)benzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-fluorobenzyl, R22 and R23 are 3-(H2NC(xe2x95x90NOH)-4-fluorobenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 3-methoxybenzyl, R22 and R23 are cyclopropylmethyl;
the compound of formula (IIaa) wherein R4 and R7 are 3-methoxybenzyl, R22 and R23 are 4-hydroxymethylbenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 3-methoxybenzyl, R22 and R23 are 3-methoxybenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 3-hydroxybenzyl, R22 and R23 are 3-hydroxybenzyl.
the compound of formula (IIaa) wherein R4 and R7 are 4-methoxybenzyl, R22 and R23 are cyclopropylmethyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-methoxybenzyl, R22 and R23 are benzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-methoxybenzyl, R22 and R23 are 2-naphthylmethyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-methoxybenzyl, R22 and R23 are 4-hydroxymethylbenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-hydroxybenzyl, R22 and R23 are benzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-methoxybenzyl, R22 and R23 are allyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-(2-hydroxyethoxy)benzyl, R22 and R23 are benzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-(2-morpholinylethoxy)benzyl, R22 and R23 are benzyl;
the compound of formula (IIaa) wherein R4 and R7 are 3-(H2NC(xe2x95x90O)CH2O)benzyl, R22 and R23 are n-butyl;
the compound of formula (IIaa) wherein R4 and R7 are 3,4-difluorobenzyl, R22 and R23 are 3-hydroxymethylbenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 3,4-difluorobenzyl, R22 and R23 are 4-hydroxymethylbenzyl;
the compound of formula (IIaa) wherein R4 and R7 are 3,4-difluorobenzyl, R22 and R23 are 3-(H2NC(xe2x95x90O))benzyl;
the compound of formula (IIaa) wherein R4 and R7 are 3,4-difluorobenzyl, R22 and R23 are 3-(H2NC(xe2x95x90NOH))benzyl;
the compound of formula (IIaa) wherein R4 and R7 are 2-naphthylmethyl, R22 and R23 are benzyl;
the compound of formula (IIaa) wherein R4 and R7 are 2-naphthylmethyl, R22 and R23 are cyclopropylmethyl;
the compound of formula (IIaa) wherein R4 and R7 are 2-thienylmethyl, R22 and R23 are cyclopropylmethyl;
the compound of formula (IIaa) wherein R4 and R7 are 2-thienylmethyl, R22 and R23 are 3-(H2NC(xe2x95x90NOH))benzyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-methylthiobenzyl, R22 and R23 are benzyl;
the compound of formula (IIaa) wherein R4 and R7 are isopropyl, R22 and R23 are n-hexyl;
the compound of formula (IIaa) wherein R4 and R7 are 4-pyridylmethyl, R22 and R23 are benzyl.
[18] Also preferred in the present invention are compounds of formula (IIb): 
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
R22 and R23 are independently selected from the group consisting of:
hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CHxe2x95x90C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(xe2x95x90O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2Nxe2x95x90CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(xe2x95x90NOH))-benzyl, (H2NNHC(xe2x95x90O))-benzyl, (H2NC(xe2x95x90O)NHNxe2x95x90CH)-benzyl, (CH3ONHC(xe2x95x90O))-benzyl, (HONHC(xe2x95x90O))-benzyl, (CH3NHC(xe2x95x90O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)-benzyl, hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(xe2x95x90O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(xe2x95x90O))-benzyl, (pyrazolyl-C(xe2x95x90O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(xe2x95x90O)NH)-benzyl, (H2NC(xe2x95x90O)NH)-benzyl, (HC(xe2x95x90O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(xe2x95x90NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(xe2x95x90NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(xe2x95x90O)O)benzyl, (CH3NHC(xe2x95x90O)O)benzyl, (NH2C(xe2x95x90O)CH2O)benzyl, (NH2C(xe2x95x90NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3Cxe2x80x94C(xe2x95x90O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(xe2x95x90NOH))benzyl, (H2NC(xe2x95x90NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl.
[19] Specifically preferred are compounds of formula (IIb): 
selected from the group consisting of:
the compound of formula (IIb) wherein R22 is 4-hydroxybenzyl and R23 is 4-hydroxybenzyl;
the compound of formula (IIb) wherein R22 is cyclopentylmethyl and R23 is cyclopentylmethyl;
the compound of formula (IIb) wherein R22 is n-butyl and R23 is n-butyl;
the compound of formula (IIb) wherein R22 is 3-hydroxybenzyl and R23 is 3-hydroxybenzyl;
the compound of formula (IIb) wherein R22 is 3-aminobenzyl and R23 is 3-aminobenzyl;
the compound of formula (IIb) wherein R22 is cyclohexylmethyl and R23 is cyclohexylmethyl;
the compound of formula (IIb) wherein R22 is cyclobutylmethyl and R23 is cyclobutylmethyl;
the compound of formula (IIb) wherein R22 is 3-hydroxymethylbenzyl and R23 is 3-hydroxymethylbenzyl;
the compound of formula (IIb) wherein R22 is 3-formylbenzyl and R23 is 3-formylbenzyl;
the compound of formula (IIb) wherein R22 is 3-formaldoximebenzyl and R23 is 3-formaldoximebenzyl.
[20] Also preferred in the present invention are compounds of the formula (Ibb): 
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
R22 and R23 are independently selected from the group consisting of:
hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CHxe2x95x90C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(xe2x95x90O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2Nxe2x95x90CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(xe2x95x90NOH))-benzyl, (H2NNHC(xe2x95x90O))-benzyl, (H2NC(xe2x95x90O)NHNxe2x95x90CH)-benzyl, (CH3ONHC(xe2x95x90O))-benzyl, (HONHC(xe2x95x90O))-benzyl, (CH3NHC(xe2x95x90O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)-benzyl, hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(xe2x95x90O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(xe2x95x90O))-benzyl, (pyrazolyl-C(xe2x95x90O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(xe2x95x90O)NH)-benzyl, (H2NC(xe2x95x90O)NH)-benzyl, (HC(xe2x95x90O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(xe2x95x90NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(xe2x95x90NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(xe2x95x90O)O)benzyl, (CH3NHC(xe2x95x90O)O)benzyl, (NH2C(xe2x95x90O)CH2O)benzyl, (NH2C(xe2x95x90NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3Cxe2x80x94C(xe2x95x90O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(xe2x95x90NOH))benzyl, (H2NC(xe2x95x90NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl.
[21] Specifically preferred are compounds of formula (Ibb): 
selected from the group consisting of:
the compound of formula (Ibb) wherein R22 is benzyl and R23 is hydrogen;
the compound of formula (Ibb) wherein R22 is cyclopropylmethyl and R23 is cyclopropylmethyl;
the compound of formula (Ibb) wherein R22 is benzyl and R23 is benzyl;
the compound of formula (Ibb) wherein R22 is 3-hydroxybenzyl and R23 is 3-hydroxybenzyl.
the compound of formula (Ibb) wherein R22 is 3-hydroxymethylbenzyl and R23 is 3-hydroxymethylbenzyl;
the compound of formula (Ibb) wherein R22 is 4-hydroxybenzyl and R23 is 4-hydroxybenzyl;
the compound of formula (Ibb) wherein R22 is 3-methoxybenzyl and R23 is 3-methoxybenzyl;
the compound of formula (Ibb) wherein R22 is 3-(H2NC(xe2x95x90NOH))benzyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (Ibb) wherein R22 is 3-(H2NC(xe2x95x90NOH))benzyl and R23 is 3-(H2NC(xe2x95x90NOH))benzyl;
the compound of formula (Ibb) wherein R22 is 3-(H2NC(xe2x95x90NOH))-4-fluorobenzyl and R23 is 3-(H2NC(xe2x95x90NOH))-4-fluorobenzyl;
[22] Also preferred in the present invention are compounds of the formula (Ic): 
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
R33 is OH, halogen, H, N3 or can alternatively be taken together with R23 to form a direct bond;
wherein R22 and R23 are independently selected from the group consisting of:
hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CHxe2x95x90C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(xe2x95x90O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2Nxe2x95x90CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(xe2x95x90NOH))-benzyl, (H2NNHC(xe2x95x90O))-benzyl, (H2NC(xe2x95x90O)NHNxe2x95x90CH)-benzyl, (CH3ONHC(xe2x95x90O))-benzyl, (HONHC(xe2x95x90O))-benzyl, (CH3NHC(xe2x95x90O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)-benzyl, hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(xe2x95x90O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(xe2x95x90O))-benzyl, (pyrazolyl-C(xe2x95x90O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(xe2x95x90O)NH)-benzyl, (H2NC(xe2x95x90O)NH)-benzyl, (HC(xe2x95x90O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(xe2x95x90NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(xe2x95x90NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(xe2x95x90O)O)benzyl, (CH3NHC(xe2x95x90O)O)benzyl, (NH2C(xe2x95x90O)CH2O)benzyl, (NH2C(xe2x95x90NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3Cxe2x80x94C(xe2x95x90O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl) aminocarbonylbenzyl (piperidinylethyl)aminocarbonylbenzyl, (H2NC(xe2x95x90NOH))benzyl, (H2NC(xe2x95x90NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl.
[23] Specifically preferred are compounds of formula (Ic): 
selected from the group consisting of:
the compound of formula (Ic) wherein R22 is 3-hydroxybenzyl, R23 is 3-hydroxybenzyl and R33 is hydrogen;
the compound of formula (Ic) wherein R22 is 3-acetylbenzyl, R23 is 3-acetylbenzyl and R33 is hydrogen;
the compound of formula (Ic) wherein R22 is 3-hydroxymethylbenzyl, R23 is 3-hydroxymethylbenzyl and R33 is hydrogen.
the compound of formula (Ic) wherein R22 is 3-(H2NC(xe2x95x90O))benzyl, R23 is 3-(H2NC(xe2x95x90O))benzyl and R33 is hydrogen.
the compound of formula (Ic) wherein R22 is 3-(H2NC(xe2x95x90NOH))benzyl, R23 is 3-(H2NC(xe2x95x90NOH))benzyl and R33 is hydrogen.
the compound of formula (Ic). wherein R22 is 3-(H2NC(xe2x95x90O))-4-fluorobenzyl, R23 is 3-(H2NC(xe2x95x90O))-4-fluorobenzyl and R33 is hydrogen.
the compound of formula (Ic) wherein R22 is 3-(H2NC(xe2x95x90NOH))-4-fluorobenzyl, R23 is 3-(H2NC(xe2x95x90NOH))-4-fluorobenzyl and R33 is hydrogen.
[24] Also preferred are compounds of formula (IId): 
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
R22 and R23 are independently selected from the group consisting of:
hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CHxe2x95x90C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(xe2x95x90O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2Nxe2x95x90CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(xe2x95x90NOH))-benzyl, (H2NNHC(xe2x95x90O))-benzyl, (H2NC(xe2x95x90O)NHNxe2x95x90CH)-benzyl, (CH3ONHC(xe2x95x90O))-benzyl, (HONHC(xe2x95x90O))-benzyl, (CH3NHC(xe2x95x90O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)-benzyl, hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(xe2x95x90O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(xe2x95x90O))-benzyl, (pyrazolyl-C(xe2x95x90O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(xe2x95x90O)NH)-benzyl, (H2NC(xe2x95x90O)NH)-benzyl, (HC(xe2x95x90O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(xe2x95x90NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(xe2x95x90NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(xe2x95x90O)O)benzyl, (CH3NHC(xe2x95x90O)O)benzyl, (NH2C(xe2x95x90O)CH2O)benzyl, (NH2C(xe2x95x90NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3Cxe2x80x94C(xe2x95x90O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(xe2x95x90NOH))benzyl, (H2NC(xe2x95x90NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl.
[25] Specifically preferred are compounds of formula (IId): 
selected from the group consisting of:
the compound of formula (IId) wherein R22 is 4-hydroxymethylbenzyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IId) wherein R22 is 3-hydroxybenzyl and R23 is 3-hydroxybenzyl;
the compound of formula (IId) wherein R22 is cyclopropylmethyl and R23 is cyclopropylmethyl;
the compound of formula (IId) wherein R22 is 2-naphthylmethyl and R23 is 2-naphthylmethyl;
the compound of formula (IId) wherein R22 is 4-hydroxybenzyl and R23 is 4-hydroxybenzyl;
the compound of formula (IId) wherein R22 is 3-aminobenzyl and R23 is 3-aminobenzyl;
the compound of formula (IId) wherein R22 is 3-hydroxymethylbenzyl and R23 is 3-hydroxymethylbenzyl;
the compound of formula (IId) wherein R22 is 3-(Me2NCH2C(xe2x95x90O)NH)-benzyl and R23 is 3-(Me2NCH2C(xe2x95x90O)NH)-benzyl;
the compound of formula (IId) wherein R22 is 3-formaldoximebenzyl and R23 is 3-formaldoximebenzyl;
the compound of formula (IId) wherein R22 is 3-(CH3C(xe2x95x90NOH))-benzyl and R23 is 3-(CH3C(xe2x95x90NOH))-benzyl;
the compound of formula (IId) wherein R22 is 3-(2-amino-4-thienyl)benzyl and R23 is 3-(2-amino-4-thienyl)benzyl;
the compound of formula (IId) wherein R22 is 5-hydroxypentyl and R23 is 5-hydroxypentyl;
the compound of formula (IId) wherein R22 is 6-hydroxypentyl and R23 is 6-hydroxypentyl;
the compound of formula (IId) wherein R22 is 5-hydroxypentyl and R23 is 2-naphthylmethyl;
the compound of formula (IId) wherein R22 is 5-hydroxypentyl and R23 is 4-hydroxymethylbenzyl;
the compound of formula (IId) wherein R22 is 5-hydroxypentyl and R23 is 3-hydroxymethylbenzyl.
[52] Also included in the present invention are compounds, or a pharmaceutically acceptable salt form thereof, selected from the following formulae: 
wherein:
R4 and R7 are independently selected from the following groups:
hydrogen; C1-C3 alkyl substituted with 0-1 R11;
R5 is xe2x80x94OR20;
R6 is hydrogen or xe2x80x94OR21;
R20 and R21 are independently hydrogen or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl;
R11 is selected from one or more of the following:
H; halogen; xe2x80x94OR13;
C3-C10 cycloalkyl substituted with 0-2 R12;
C1-C4 alkyl substituted with 0-2 R12;
aryl(C1-C3 alkyl) substituted with 0-2 R12;
aryl substituted with 0-2 R12; or
a heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring system being substituted with 0-2 R12;
R12, when a substituent on carbon, is selected from one or more of the following:
benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3, 2-(1-morpholino)ethoxy, xe2x80x94CO2H, hydroxamic acid, hydrazide, xe2x80x94C(R14)xe2x95x90N(OR14), cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with xe2x80x94NR13R14, xe2x80x94NR13R14, hydroxy, hydroxymethyl; or
R12, when a substituent on nitrogen, is methyl;
R13 is H, C1-C4 alkyl, C2-C4 alkenyl, or benzyl;
R14 is OH, H, CF3, C1-C4 alkyl, C1-C4 alkoxy, NH2, C2-C4 alkenyl, or benzyl;
R13 and R14 can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(R15)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94;
R15 is H or CH3;
R22 and R23 are independently selected from the following:
hydrogen;
C1-C8 alkyl substituted with 0-3 R31;
C2-C6 alkenyl substituted with 0-3 R31;
C2-C4 alkynyl substituted with 0-3 R31;
R31 is selected from one or more of the following:
halogen, xe2x80x94OR13, C1-C4 alkyl, C3-C10 cycloalkyl, xe2x80x94C(R14)xe2x95x90N(OR14), xe2x80x94CO2R13, xe2x80x94S(O)mR13;
aryl substituted with 0-5 R32; or
a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring being substituted with 0-2 R32;
R32, when a substituent on carbon, is selected from one or more of the following:
benzyloxy, halogen, 2-(1-morpholino)ethoxy, xe2x80x94CO2R13, hydroxamic acid, xe2x80x94CONR13NR13R14, cyano, boronic acid, sulfonamide, xe2x80x94CHO, C3-C6 cycloalkoxy, xe2x80x94NR13R14, xe2x80x94C(R14)xe2x95x90N(OR14), NO2, xe2x80x94OR13, xe2x80x94NR40R41, xe2x80x94SOmR13, xe2x80x94SOmNR13R14, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94OC(xe2x95x90O)NR13R14, xe2x80x94C(xe2x95x90O)R11, xe2x80x94OC(xe2x95x90O)R11, xe2x80x94OCO2R13, phenyl, xe2x80x94C(xe2x95x90O)NR13xe2x80x94(C1-C4 alkyl)-NR13R14, xe2x80x94C(xe2x95x90O)NR40R41, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C1-C4 haloalkynyl, xe2x80x94C(xe2x95x90O)NR13R14; xe2x80x94C(xe2x95x90O)C(R11)2NR13R14; xe2x80x94C(xe2x95x90O)C(R11)2NR13NR14; xe2x80x94C(xe2x95x90O)C(R11)2NR13CO2R13; xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13R14; xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)xe2x80x94NR13CO2R13; or
C1-C4 alkoxy substituted with 0-3 groups selected from: R11, C3-C6 cycloalkyl, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94NR13R14 or OH;
C1-C4 alkyl substituted with 0-3 groups selected from: R11, xe2x95x90NR14, xe2x95x90NNR13C(xe2x95x90O)NR13R14 or xe2x80x94NR13R14;
C2-C4 alkenyl substituted with 0-3 R11;
C2-C4 alkynyl substituted with 0-3 R11;
a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur substituted with 0-2 R12;
R32, when a substituent on nitrogen, is methyl;
m is 0, 1, or 2;
R36 is selected from: C1-C2 alkyl; COR37; NR38R39; CN; CCl3;
R37 is selected from:
hydrogen;
C1-C2 alkyl substituted with 0-1 R11;
hydroxyl;
C1-C2 alkoxy substituted with 0-1 R11;
xe2x80x94NR38R39;
R38 and R39 are independently selected from:
hydrogen;
C1-C2 alkyl substituted with 0-3 R11; or
an amine protecting group;
R40 is selected from: H, C1-C3 alkyl;
R41 is selected from:
xe2x80x94C(xe2x95x90O)NR13R14;
xe2x80x94C(xe2x95x90O)NR13NR14;
xe2x80x94C(xe2x95x90O)C(R11)2NR13R14;
xe2x80x94C(xe2x95x90O)C(R11)2NR13NR14;
xe2x80x94C(xe2x95x90O)C(R11)2NR13CO2R13;
xe2x80x94C(xe2x95x90O)H;
xe2x80x94C(xe2x95x90O)R11;
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)-NR13R14;
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl)-NR13CO2R13;
1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus.
[53] Another aspect of the invention is a process for preparing cyclic compounds of formula (I): 
wherein:
W is selected from:
xe2x80x94N(R22)C(xe2x95x90O)N(R23)xe2x80x94;
xe2x80x94N(R22)C(xe2x95x90S) N(R23)xe2x80x94;
xe2x80x94N(R22)S(xe2x95x90O)2N(R23)xe2x80x94;
R22 and R23 are as defined above, provided that at least one of R22 or R23 must be H;
R4, R4A, R7, R7A, R5a, and R6a are as defined above;
n is 0, 1, or 2;
R20 and R21 are as defined above and may in addition be selected from a hydroxyl protecting group;
said process comprising the step of reacting an acyclic diamine compound of the formula (III): 
with a suitable cyclizing reagent in a suitable solvent, said solvent optionally comprising a base, thereby to form a compound of formula (I).
For compounds of formula (I) wherein W is xe2x80x94N(R22)C(xe2x95x90O)N(R23)xe2x80x94, the suitable cyclizing reagent may be selected from, but is not limited to, phenyl chloroformate, phenyl tetrazoylformate, urea, phosgene, triphosgene, oxalyl chloride, N,Nxe2x80x2-disuccinimidyl carbonate, 1,1xe2x80x2-carbonyldiimidazole, trichloromethyl chloroformate, and 2(S),3-pyridinediyl thiocarbonate. A preferred cyclizing reagent is 1,1xe2x80x2-carbonyl diimidazole.
For compounds of formula (I) wherein W is xe2x80x94N(R22)C(xe2x95x90S)N(R23)xe2x80x94, the suitable cyclizing reagent may be selected from, but is not limited to, 1,1xe2x80x2-thiocarbonyl diimidazole or carbon disulfide. Preferably, the cyclizing reagent is 1,1xe2x80x2-thiocarbonyldiimidazole.
For compounds of formula (I) wherein W is xe2x80x94N(R22)S(xe2x95x90O)2N(R23)xe2x80x94, the suitable cyclizing reagent may be selected from, but is not limited to, sulfamide.
A base may optionally be included in the above-described method in order to account for the lability of the R20 and R21 hydroxyl protecting groups to the cyclization conditions. The base may be selected from organic bases which include, but are not limited to, pyridine, diisopropylethylamine, and triethylamine. The base may alternatively be selected from inorganic bases which include but are not limited to sodium hydroxide.
The above-described reaction is carried out in a suitable solvent, for example, in an organic solvent or in a biphasic suspension of water and an organic solvent. Suitable solvents include chlorinated organic solvents which include, but are not limited to, chloroform, methylene chloride, tetrachloroethane, butyl chloride and dichloroethane. A preferrable chlorinated organic solvent is chloroform. The non-chlorinated organic solvents useful in the method of the invention include, but are not limited to tetrahydrofuran, N,N-dimethylformamide and toluene. A preferrable non-chlorinated organic solvent is toluene.
The reaction can be conducted at a temperature of from about 0xc2x0 C. to about the boiling point of the solvent selected, 153xc2x0 C. in the case of N,N-dimethylformamide. Preferably, the temperature of the reaction is about 0xc2x0 C. to about room temperature.
The time required for completion of the reaction can range from about 1 hour to about 5 days, depending on the combination of cyclizing reagent, solvent, base and stereoisomer of compound (III) selected. The reaction can be run under nitrogen or other inert atmosphere, provided that any changes in concentration and integrity of the reagents due to decomposition are compensated for.
As used herein, the term xe2x80x9chydroxyl protecting groupxe2x80x9d means any group known in the art of organic synthesis for the protection of hydroxyl groups. Such protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York (1991), the disclosure of which is hereby incorporated by reference. The hydroxyl protecting groups are base-stable and can include, but are not limited to acyl types, aromatic carbamate types and alkyl types. Exemplary are methyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, triphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, pivaloate or N-phenylcarbamate.
[55] Another aspect of the invention is a process for preparing cyclic compounds of formula (Icc): 
wherein:
R4, R7, R20, R22, R23 are as defined above, and R33 is hydrogen or halogen;
with the proviso that neither R22 or R23 are hydrogen.
said process comprising the step of reacting a cyclic urea of formula (IIaaa) 
with a reagent capable of converting the free hydroxy in the compound of formula (IIaaa) to a suitable leaving group and, at the same time, providing in situ a suitable nucleohilic species to bring about a ring contraction, in a suitable solvent, thereby to form a compound of formula (Icc).
The above reagent may be selected from, but is not limited to, 2-acetoxyisobutyryl bromide, DAST, or a combination of triphenylphosphine/DEAD/chloroacetic acid. The preferred reagent when R20 and R33 are hydrogen is 2-acetoxyisobutyryl bromide.
The above-described reaction is carried out in a suitable solvent, for example, in an organic solvent. Suitable solvents include chlorinated organic solvents which include, but are not limited to, chloroform, methylene chloride, tetrachloroethane, butyl chloride and dichloroethane. A preferrable chlorinated organic solvent is dichloromethane. The non-chlorinated organic solvents useful in the method of the invention include, but are not limited to tetrahydrofuran, diethyl ether and toluene. A preferrable non-chlorinated organic solvent is tetrahydrofuran.
The reaction can be conducted at a temperature of from about 0xc2x0 C. to 50xc2x0 C. Preferably, the temperature of the reaction is about 0xc2x0 C. to about room temperature.
The time required for completion of the reaction can range from about 5 min to about 24 hr, depending on the combination of solvent, and substitution on compound (IIaaa) selected. The reaction can be run under nitrogen or other inert atmosphere, provided that any changes in concentration and integrity of the reagents due to decomposition are compensated for.
For compounds of Formula (1cc) wherein R33 is hydrogen, a second step comprising reacting a compound of formula (1cc), wherein R33 is bromo, with a suitable dehalogenation reagent is required. Suitable dehalogenation reagents may be selected from but are not limited to tri-n-butyltin hydride or zinc dust. Preferred reagents are tri-n-butyltin hydride or zinc. Suitable solvents in the case of tri-n-butyltin hydride include toluene, tetrahydrofuran or benzene, with the preferred solvent being toluene. The reaction may be carried out at a temperature of from about 50xc2x0 C. to about 120xc2x0 C. Preferably, the temperature of the reations is from 80xc2x0 C. to 120xc2x0 C. The time required for completion of the reaction is from about 30 min to about 6 hr. In the case where the reagent used is zinc dust, then the preferred solvent is glacial acetic acid, the prefferred temperature is room temperature, and the time required for completion of reaction is from about 1 hr to about 48 hr.
Hereby incorporated herein by reference is copending commonly assigned U.S. patent application Ser. No. of Jadhav and Emmett 08/040,146 filed Mar. 30, 1993.
In the present invention it has been discovered that the compounds of formula (I) above are useful as inhibitors of HIV protease and similar retroviral proteases, and for the inhibition of HIV and the treatment of HIV infection and similar retrovirus infections.
The present invention also provides methods for the treatment of HIV infection by administering to a host infected with HIV a pharmaceutically or therapeutically effective or acceptable amount of a compound of formula (I) as described above. By therapeutically effective amount, it is meant an amount of a compound of the present invention effective to inhibit HIV infection or treat the symptoms of HIV infection in a host.
The compounds of formula (I) of the present invention are also useful for the inhibition of HIV in an ex vivo sample containing HIV or expected to be exposed to HIV. Thus, the compounds of the present invention may be used to inhibit HIV present in a body fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV.
The compounds provided by this invention are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral replication and/or HIV protease, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.
Since the compounds of the present invention exhibit specificity for HIV protease, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV protease. Thus, inhibition of the protease activity in an assay (such as the assays described herein) by a compound of the present invention would be indicative of the presence of HIV protease and HIV virus.
The compounds herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that certain compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. Also, it is realized that cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When any variable (for example, R1 through R41, R4A and R7A, m, n, W, Z, etc.) occurs more than one time in any constituent or in formula (I) or (II), or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R11, then said group may optionally be substituted with up to three R11 and R11 at each occurrence is selected independently from the defined list of possible R11. Also, for example, in xe2x80x94N(R20)2, each of the R20 substituents may be independently selected from the list of possible R20 groups defined. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. Similarly, by way of example, for the group xe2x80x94C(R11)2xe2x80x94, each of the two R11 substituents on C is independently selected from the defined list of possible R11.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)); xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl; and xe2x80x9cbiycloalkylxe2x80x9d is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like; and xe2x80x9calkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon. bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
The terms xe2x80x9c-(alkyl)-xe2x80x9d n, xe2x80x9c-(alkyenyl)-xe2x80x9d, xe2x80x9c-(phenyl)-xe2x80x9d, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I. Such groups may alternatively and equivalently be denoted as xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, respectively.
xe2x80x9cAlkylcarbonylxe2x80x9d is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to the residue of the compound at the designated location. xe2x80x9cAlkylcarbonylaminoxe2x80x9d is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to an amino bridge, where the bridge is attached to the residue of the compound at the designated location. xe2x80x9cAlkylcarbonyloxyxe2x80x9d is intended to include an alkyl group of an indicated number of carbon atoms attached to a carbonyl group, where the carbonyl group is attached through an oxygen atom to the residue of the compound at the designated location.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to mean phenyl or naphthyl; the term xe2x80x9carylalkylxe2x80x9d represents an aryl group attached through an alkyl bridge. By way of examples: the term xe2x80x9cC7-C10 arylalkylxe2x80x9d is intended to refer to an aryl group attached through a C1-C4 alkyl bridge to the residue of the indicated compound; the term xe2x80x9c(C1-C3 alkyl)arylxe2x80x9d is intended to refer to a C1-C3 alkyl group which is attached through an aryl ring to the residue of the indicated compound; the term xe2x80x9caryl(C1-C3 alkyl)xe2x80x9d is intended to refer to an aryl group attached through a C1-C3 alkyl group to the residue of the indicated compound.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of formula I, then such substituent may be bonded via any atom in such substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise, said piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of formula (I) via any atom in such piperazinyl, piperidinyl, tetrazolyl group.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that an one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
As used herein, the term xe2x80x9cany group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulfhydrylxe2x80x9d means any group bonded to an O, N, or S atom, respectively, which is cleaved from the O, N, or S atom when the compound is administered to a mammalian subject to provide a compound having a remaining free hydroxyl, amino, or sulfhydryl group, respectively. Examples of groups that, when administered to a mammalian subject, are cleaved to form a free hydroxyl, amino or sulfhydryl, include but are not limited to, phosphate esters, C1-C6 alkyl substituted with 0-3 R11, C3-C6 alkoxyalkyl substituted with 0-3 R11, C1-C6 alkylcarbonyl substituted with 0-3 R11, C1-C6 alkoxycarbonyl substituted with 0-3 R11, C1-C6 alkylaminocarbonyl substituted with 0-3 R11, benzoyl substituted with 0-3 R12, phenoxycarbonyl substituted with 0-3 R12, phenylaminocarbonyl substituted with 0-3 R12, or heteroarylcarbonyl. Examples of groups that, when administered to a mammalian subject, are cleaved to form a free hydroxyl, amino or sulfhydryl, may include hydroxy, amine or sulfhydryl protecting groups, respectively.
As used herein, the term xe2x80x9camine protecting groupxe2x80x9d means any group known in the art of organic synthesis for the protection of amine groups. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biologyxe2x80x9d, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) fair, and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
By a xe2x80x9cketal ringxe2x80x9d or xe2x80x9cketalxe2x80x9d group is meant any ketal protecting group which can be hydroyzed to form a carbonyl. Such ketal rings or ketal protecting groups are well known in the art of organic synthesis and typically include, for example, substituted or unsubstituted carbocyclic diethers, dithioethers, or mixed ethers. Such ketal protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991).
The term xe2x80x9camino acidxe2x80x9d as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids, modified and unusual amino acids, as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids,such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, 9-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methylnorleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
The term xe2x80x9camino acid residuexe2x80x9d as used herein means that portion of an amino acid (as defined herein) that is present in a peptide.
The term xe2x80x9cpeptidexe2x80x9d as used herein means a compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond. The term xe2x80x9cpeptidexe2x80x9d also includes compounds containing both peptide and non-peptide components, such as pseudopeptide or peptide mimetic residues or other non-amino acid components. Such a compound containing both peptide and non-peptide components may also be referred to as a xe2x80x9cpeptide analogxe2x80x9d.
The term xe2x80x9cpeptide bondxe2x80x9d means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound of formula (I) is modified by making acid or base salts of the compound of formula (I). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of formula (I) wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, or benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I); phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol and phenol functional groups in the compounds of formula (I); and the like.
The pharmaceutically acceptable salts of the compounds of formula (I) include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of formula (I) formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of formula (I) which contain a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
As used herein, xe2x80x9cWxe2x80x9d is not intended to be a symbol for tungsten.
The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below.
The compounds of the present invention may be synthesized using the general synthetic procedures described below. Each of the references cited below are hereby incorporated herein by reference. All the temperatures are reported herein in degrees Celsius.
Compounds of the invention wherein:
W is xe2x80x94N(R22)C(xe2x95x90Z)N(R23)xe2x80x94 or xe2x80x94N(R22)C(xe2x95x90O)C(xe2x95x90O)N(R23)xe2x80x94 or xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)N(R23)xe2x80x94 or xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)2N(R23)xe2x80x94 or xe2x80x94N(R22)P(xe2x95x90O)(R24a)N(R23)xe2x80x94 or xe2x80x94N(R22)C(F2)C(xe2x95x90O)N(R23)xe2x80x94 or xe2x80x94N(R22)C(F2)S(xe2x95x90O)N(R23)xe2x80x94;
R5 is xe2x80x94OR20 or H;
R6 is xe2x80x94OR21 or H; and
n is 1; can be formed from diamines of formula (III): 
The diamines of formula (III) can be synthesized as described in copending commonly assigned patent application Jadhav et al. U.S. Ser. No. 07/714,042, filed May. 31, 1991. Alternative methods which can be used to synthesize the compounds of structure (III) above are described in European Patent Application Publication Number 402646A1, U.S. Pat. No. 4,837,204, and Canadian Patent Application 2,026,832.
The compounds of formula (III) can be cyclized to form compounds of formula (IV) under conditions normally used to form cyclic ureas, as is known to one skilled in the art. Reagents Jxe2x80x94(Cxe2x95x90Z)xe2x80x94Jxe2x80x2, where J and Jxe2x80x2 are leaving groups, are employed, preferably under relatively dilute conditions (for example, less than about 0.1 M), to effect ring closure to provide compounds of formula (I). Many examples of J and Jxe2x80x2 are known; preferred are carbonyl diimidazole, thiocarbonyldiimidazole, phosgene, thiophosgene, diphenyl carbonate, or diphenyl thiocarbonate. Additionally, for compounds wherein W is xe2x80x94N(R22)C(xe2x95x90O)C(xe2x95x90O)N(R23)xe2x80x94, compounds of formula (III) can be reacted with activated derivatives of oxalic acid, preferably oxalyl chloride, under the above conditions to form the diamide.
For compounds of the invention where R20 or R21 is xe2x80x94OH, it is advantageous to protect the free hydroxyl before cyclization. Protecting groups used can include any of those listed in Greene and Wuts, Protective Groups in Organic Synthesis, Chapter 2, Wiley, NY (1991). The preferred protecting groups are trimethylsilylethoxymethyl (SEM), methoxyethoxymethyl (MEM), or methoxymethyl (MOM).
Cyclization of compounds of formula (III) results in structure (IV) (i.e., structure (I) wherein W is xe2x80x94N(R22)C(xe2x95x90O)C(xe2x95x90O)N(R23)xe2x80x94 and n is 1). 
Another, preferred method to form compounds of formula (IV), in cases wherein R22 and R23 are linked to their respective nitrogens by a CH2 residue, is to cyclize a compound of structure (III) where R22 and R23 are hydrogen, and to alkylate the nitrogens using a base, a phase transfer catalyst, and an alkylating agent, using methods well known in the art. The preferred base is sodium hydride, and the preferred alkylating agents are R22Y and R23Y, wherein Y is a halogen, triflate, or mesylate, preferably a bromide or iodide. Preferred conditions are in polar aprotic solvents between 0 and 100xc2x0 C.
Cleavage of protecting groups, if employed, yields structures of formula (I) wherein R5 and R6 are hydroxyl.
When R5 and R6 are other than OR20 and OR21, some chemical manipulation of functional groups may need to be performed in the preparation of the compounds of formula (III) or (IV), as is appreciated by one of skill in the art of organic synthesis. Described below are examples of such procedures.
Methods for obtaining compounds wherein R5 is OH and R6 is OR21 include protection of nitrogen, if necessary, followed by reaction of the diol with one equivalent of base and one equivalent of acyl halide, alkyl halide, alkoxyalkyl halide, alkoxycarbonyl halide, benzoyl halide, diphenyl carbonate or phenylisocyanate, and purification by column chromatography of the unwanted bis-alkylated and unreacted material.
Methods for obtaining compounds wherein R5 is OH and R6 is H include protection of nitrogen, if necessary, and reduction of the diol to the monool using techniques known in the art (see, for example, Chem. Comm. 1971, 1097; J. Org. Chem. 1969, 3923). The preferred method is formation of cyclic diol ester and reduction using hydride. Deprotection of nitrogen, if necessary, results in the desired compound.
Methods for obtaining compounds wherein R5 is OH and R6 is F include protection of nitrogen, if necessary, followed by formation of mono-protected diol as described above. Reaction with a fluorinating agent, preferably diethylaminosulfurtrifluoride (DAST) (Reagents for Organic Synthesis, Vol. 13, p. 110, Wiley Interscience, NY, 1988), provides the alkyl fluoride. Deprotection of nitrogen, if necessary, and hydroxyl results in the desired compound.
Methods for obtaining compounds wherein R5 is OH and R6 is xe2x95x90O include protection of nitrogen, if necessary, and standard conditions for oxidizing glycols to pinacols. The preferred oxidant is one equivalent of pyridinium dichromate in dichloromethane, or one equivalent of NaOCl in HOAc. Deprotection of nitrogen, if necessary, results in the desired compound. Alternatively, a monohydroxy compound described above can be oxidized to the ketone under standard conditions, preferably Swern oxidation using oxalyl chloride, DMSO and Et3N, followed by alpha-hydroxylation of the ketone (see Tet. Lett. 1981, 607; Tet. Lett. 1982, 2917).
Methods for obtaining compounds wherein R5 is OH and R6 is difluoro include protection of nitrogen, if necessary, and hydroxyl of the above obtained pinacol, followed by reaction of the carbonyl with a fluorinating reagent, such as DAST. Deprotection of hydroxyl and nitrogen, if necessary, results in the desired compound.
Methods for obtaining compounds wherein R5 and R6 join to form an epoxide include protection of nitrogen, if necessary, followed by standard conditions for the formation of an epoxide from a glycol (see, for example, J. Org. Chem. 1981, 3361). Preferred is the reaction of the glycol with more than 2 equivalents of base and one equivalent of an activating group, such as methanesulfonyl chloride. Deprotection if necessary results in the desired compound.
Methods for obtaining compounds wherein R5 is OH and R6 is C1-C3 alkyl include protection of nitrogen, if necessary, and reaction of the epoxide prepared above with C1-C3 alkylmetal reagents. Preferred is the reaction of lithium dialkyl cuprates in aprotic solvents at low temperatures (xe2x88x9278 to xe2x88x9240xc2x0 C.) (see Carruthers, Some Modern Methods in Organic Synthesis, p. 64, Cambridge University Press, 1978).
With a judicious selection of reagents, as is well appreciated to one skilled in the art, these manipulations can be performed in a straightforward manner to yield the claimed combinations of R5 and R6.
Compounds of the invention wherein:
W is xe2x80x94N(R22)C(xe2x95x90Z)N(R23)xe2x80x94 or xe2x80x94N(R22)C(xe2x95x90O)C(xe2x95x90O)N(R23)xe2x80x94or xe2x80x94N(R22)S(xe2x95x90Zxe2x80x2)N(R23)xe2x80x94 or xe2x80x94N(R22)S(xe2x95x90Z)2N(R23)xe2x80x94 or xe2x80x94N(R22)P(xe2x95x90O)(R24a)N(R23)xe2x80x94 or xe2x80x94N(R22)C(F2)C(xe2x95x90O)N(R23)xe2x80x94 or xe2x80x94N(R22)C(F2)S(xe2x95x90O)N(R23)xe2x80x94 or xe2x80x94N(R22)P(xe2x80x94Z)N(R23)xe2x80x94, and n is 0;
can be synthesized from diamines of formula (V): 
which can in turn be synthesized as described in European Patent Application Publication Number 402 646 A1.
Protection, if necessary, cyclization, and functional group manipulation if desired is performed as described above to obtain compounds of structure (VI): 
Compounds of the invention wherein:
W is xe2x80x94OC(xe2x95x90O)Oxe2x80x94 or xe2x80x94C(xe2x95x90Z)xe2x80x94 or xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)C(R27)(R28)xe2x80x94 or xe2x80x94P(xe2x95x90O)(R24a)xe2x80x94 and n is 1;
can be formed from diols of structure (VII): 
which can in turn be synthesized as described in copending, commonly assigned U.S. patent application Jadhav et al. U.S. Ser. No. 07/714,042, filed May. 31, 1991.
Functional group manipulation, if desired, may be performed as described above, followed by cyclization to the carbonate using standard conditions, preferably phosgene or thiophosgene in the presence of 2 equivalents of a base such as potassium hydride, to obtain compounds of structure (I).
Compounds of the invention wherein:
W is xe2x80x94N(R22)C(xe2x95x90Z)Oxe2x80x94 or N(R22)P(xe2x95x90O)(R24a)C(R27)(R28)xe2x80x94 or xe2x80x94C(R25)(R26)P(xe2x95x90O))(R24a)Oxe2x80x94 and n is 1;
can be formed from aminoalcohol of structure (VIII): 
which can in turn be synthesized as described in a copending, commonly assigned U.S. patent application Jadhav et al. U.S. Ser. No. 07/714,042, filed May. 31, 1991, by employing a single equivalent of azide in the reaction of the diol of formula (VII) to obtain the azidoalcohol, followed by reduction as described in U.S. Ser. No. 07/714,042, to form the aminoalcohol.
Protection, if necessary, and functional group manipulation, if desired, is performed as described above, followed by cyclization to the carbamate using standard conditions, preferably phosgene or thiophosgene in the presence of 2 equivalents of a base, such as potassium hydride, to obtain compounds of structure (I).
Compounds of the invention wherein:
W is xe2x80x94OC(xe2x95x90Z)Oxe2x80x94 and n is 0;
can be formed from the diol of structure (IX): 
which can in turn be synthesized by the reaction of R4CHO with the lithium anion of 1,3 dithiane, followed by the reaction of R7CHO with the anion of the product (see Carruthers, Some Modern Methods in Organic Synthesis, p. 45, Cambridge University Press, 1978). Cleavage of the dithiane with mercuric ion yields the acyclic alpha, alphaxe2x80x2 dihydroxyketone.
Functional group manipulation, if desired, is performed as described above, followed by cyclization to the carbonate using standard conditions, preferably phosgene or thiophosgene, in the presence of 2 equivalents of a base such as potassium hydride, to obtain compounds of structure (I).
Compounds of the invention wherein:
W is xe2x80x94N(R22)C(xe2x95x90Z)Oxe2x80x94 and n is 0;
can be formed from aminoalcohol of structure (X): 
which can in turn be synthesized by the techniques described in European Patent Application Publication Number 402 646 A1 for the synthesis of compounds of structure (V), above; however, in place of azide, in opening the oxirane (shown below), an oxygen nucleophile, such as acetate or hydroxide ion, is reacted in the presence of a polar aprotic solvent, such as DMSO. 
Alternatively, the oxirane is treated with a catalytic amount of a strong acid in water and a cosolvent, if necessary, which technique also removes the BOC protecting group.
Protection, if necessary, and functional group manipulation, if desired, is performed as described above, followed by cyclization to. the carbamate using standard conditions, preferably phosgene or thiophosgene in the presence of 2 equivalents of a base such as potassium hydride, to obtain compounds of structure (I).
Compounds of the present invention wherein:
W is xe2x80x94C(R25)(R26)N(CH3)(O)C(R27)(R28)xe2x80x94;
can be synthesized from aminoalcohols (VIII) and (X) by the following steps: protection of nitrogen, if necessary, preferably with a benzyloxycarbonyl group; activation of the alcohol to displacement, preferably with a sulfonate derivative, such as mesyl chloride; removal of the nitrogen protecting group, preferably with hydrogen in the presence of a catalyst, such as palladium on carbon; and heating under dilute conditions in the presence of a base such as triethylamine to effect cyclization.
The secondary cyclic amine is then methylated, preferably with formic acid/formaldehyde, and oxidized, preferably with a peracid, such as MCPBA, to form compounds of formula (I), wherein W is xe2x80x94C(R25)(R26)N(CH3)(O)C(R27)(R28)xe2x80x94. The secondary cyclic amine can alternatively be directly oxidized to form structure (I), where W is xe2x80x94C(R25)(R26)N(OR29)C(R27)(R28)xe2x80x94.
Compounds wherein:
W is xe2x80x94C(R25)(R26)C(xe2x95x90Z)C(R27)(R28)xe2x80x94 and n is 0;
can be prepared by the alkylation of protected cyclohexanedione (XI) with the required R4-LG and R7-LG, and optionally R4A-LG and R7A-LG groups, wherein LG represents a leaving group such as halogen or sulfonate ester. 
Reduction of the ketone to the alcohol, preferably with LiAlH4, or manipulation to other values of R5 as described above, is followed by cleavage of the ketal (see Greene and Wuts, Protective Groups in Organic Synthesis, Chapter 2, Wiley, NY, 1991). Protection of the alcohol or other reactive groups, followed by alkylation ketone and deprotection, provides compounds of structure (I), wherein W is xe2x80x94C(R25)(R26)C(xe2x95x90Z)C(R27)(R28)xe2x80x94 and n is 0.
Compounds wherein:
W is xe2x80x94C(R25)(R26)C(xe2x95x90Z)C(R27)(R28)xe2x80x94 and n is 1;
can be prepared from the protected hydroxyketones described immediately above by ring expansion, for example via the Tiffeneau-Demyanov reaction (March, Advanced Organic Chemistry, p. 965, Wiley, NY, 1985), or by treatment with dimethylsulfonium ylide to form the spiro-epoxide, followed by acid-catalyzed ring expansion to the cycloheptanone (ibid., pp. 871, 966).
The above routes have the advantage of producing a number of stereoiomers which, upon purification, can be evaluated for the best combination of potency, safety and in vivo availability.
Compounds wherein:
W is xe2x80x94C(R25)(R26)C(F2)C(R27)(R28)xe2x80x94 and n is 0 or 1;
can be obtained from the above-described protected hydroxyketone by treatment with a fluorinating reagent, preferably DAST, as described above.
Compounds wherein:
W is xe2x80x94N(R22)C(xe2x95x90Z)C(R27)(R28)xe2x80x94 and n is 0;
can be obtained by cyclization of compound (XII) to the lactam using techniques known in the art (March, Advanced Organic Chemistry, p. 371, Wiley, NY, 1985). 
Compounds of structure (XII) can in turn be obtained as described in European Patent Application Publication Number 434 365 A2, European Patent Application Publication Number 386 611 A2, European Patent Application Publication Number 389 127 A1, and CA 2005337, each of which are hereby incorporated by reference. OP in structure (XII) designates protected oxygen. Hydroxyl can be protected by the use of any of a number of groups as described in Greene and Wuts, Protective Groups in Organic Synthesis, Chapter 2, Wiley, NY (1991).
If desired, the resulting lactam (XIII): 
can be further functionalized, for example by the following techniques: the lactam nitrogen can be alkylated with an R22-LG group, preferably employing sodium hydride in DMF; an R4A, R7 or R7A group can be added by deprotection and oxidation of the alcohol, followed by alkylation of the enolate using R4A-LG, R7-LG or R7A-LG; and reduction of the ketone to hydroxyl or otherwise functionalizing to obtain the R5 group of choice as described above.
Compounds wherein:
W is xe2x80x94N(R22)C(xe2x95x90Z)C(R27)(R28)xe2x80x94 and n is 1;
can be obtained through techniques known in the art from ketones of structure (I) wherein W is xe2x80x94C(R25)(R26)C(xe2x95x90Z)C(R27)(R28)xe2x80x94 and n is 0, preferably via the Beckmann rearrangement (March, Advanced Organic Chemistry, p. 987, Wiley, NY, 1985). Manipulation of the R5 group, if desired, as described above provides R5 and R6-substituted examples of (I), wherein W=xe2x80x94N(R22)C(xe2x95x90Z)C(R27)(R28)xe2x80x94 and n=1.
Compounds wherein:
W is xe2x80x94C(R25)(R26)C(xe2x95x90Z)Oxe2x80x94 and n is 0 or 1;
can be obtained from compounds of structure (I), wherein W=xe2x80x94N(R22)C(xe2x95x90Z)C(R27)(R28)xe2x80x94, n=0 or 1, and R22=H. for example, by hydrolysis of the lactam, followed by displacement of the primary amine by hydroxyl, and closure to the lactone (March, Advanced Organic Chemistry, p. 348, Wiley, NY, 1985).
Similarly, compounds wherein:
W is xe2x80x94C(R25)(R26)C(xe2x95x90Z)Sxe2x80x94 and n is 0 or 1;
can be obtained from compounds of structure (I), wherein W=xe2x80x94N(R22)C(xe2x95x90Z)C(R27)(R28)xe2x80x94, n=0 or 1, and R22=H, for example, by hydrolysis of the lactam, followed by conversion of the primary amine to the diazonium salt, displacement by NaSH, and closure to the thiolactone (March, Advanced Organic Chemistry, p. 601, Wiley, NY, 1985).
Compounds of structure (I) described above wherein Z=0 can be converted to the thio derivatives, Z=S, using standard conditions (March, Advanced Organic Chemistry, p. 792, Wiley, NY, 1985); preferred is the use of the disulfide described in Bull. Soc. Chim. Belges 1978, 223.
Structures (I) described above wherein Z=0 can be converted to the imino derivatives, Z=NR24, using standard conditions. When R24 is OH or O-alkyl, the oximes can be formed and alkylated if desired as described in March, Advanced Organic Chemistry, pp. 359, 805, Wiley, NY, 1985. The hydrazones and imines can be formed similarly (ibid, pp. 533, 797).
The compounds of the formula (I) where in W=xe2x80x94N(R22)P(O)(R24a)N(R23)xe2x80x94 and n=1, and R24a is ethyl, can be synthesized by cyclization of diamine III under conditions normally used to form cyclic phosphoric amides, as exemplfied by Patois et al. in Heteroatom. Chem. 1(5), 369-374, (1990), wherein ethyl phosphorodichloridate in presence of trialkylamine, such as triethylamine, was used to cyclize a diimino derivative. Similarly, other diimines could be cyclized to form cyclic phosphoric amide derivatives.
It is expected that the compounds of the invention can also be prepared as shown in Scheme 1 (shown below). The intra-molecular coupling of the N-substituted or unsubstituted dialdehydes may be achieved by organometal reagents derived from vanadium, titanium, samarium etc. The dialdehyde precursors can be prepared from the commercially available materials by the methods known to those skilled in the art of organic synthesis, preferably by the techniques disclosed in copending commmonly assigned U.S. patent application, Hodge, U.S. Ser. No. 07/659,442, filed Feb. 21, 1991.
Compounds wherein W is xe2x80x94N(R22)C(xe2x95x90O)N(R23)xe2x80x94 and n is 2 can be synthesized as shown in Scheme 2 (below). The eight-membered cyclic urea in Scheme 2 can be protected, if necessary, and manipulated as described above to yield the desired compounds.
Compounds wherein W is xe2x80x94N(R22)C(xe2x95x90O)N(R23)xe2x80x94 and n is 1 can likewise be synthesized as shown in Schemes 3, 4, 6, 7 (below). If necessary, intermediates described herein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.
Compounds wherein W is xe2x80x94N(R22)C(xe2x95x90Nxe2x80x94OR)N(R23)xe2x80x94 or xe2x80x94N(R22)C(xe2x95x90S)N(R23)xe2x80x94 and n is 1 can be synthesized as shown in Scheme 5 (below). If necessary, intermediates described herein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.
Compounds wherein W is xe2x80x94N(R22)C(xe2x95x90O)N(R23)xe2x80x94 and n is 0 can likewise be synthesized as shown in Scheme 8 (below). If necessary, intermediates described herein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.
Compounds wherein W is xe2x80x94N(R22)C(xe2x95x90O)N(R23)xe2x80x94, n is 0 and R23 and R33 are combined to be a direct bond, can be synthesized as shown in Scheme 9. Compounds of (XXXIIa) were treated under strongly ionizing conditions to produce compounds where W is xe2x80x94N(R22)C(xe2x95x90O)N(R23)xe2x80x94, n is 0, and R23 is H, R33 is xe2x80x94O2C-alkyl. Treatment of compound (XXXIIa) with hydrogen and palladium catalyst provided R33 is H, whereas treatment with gaseous hydrogen bromide provided R33 is Br. Another route to these compounds was developed (Scheme 10). If necessary, intermediates described herein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.
Compounds wherein W is xe2x80x94N(R22)S(xe2x95x90O)2N(R23)xe2x80x94, n is 1 could be synthesized as shown in Scheme 11. Diamines of structure (III) were treated with sulfamide to give the cyclic sulfamides. Alkylation using a metal hydride base gave the bisalkylated products. The monoalkylated products could be obtained by selective alkylation using techniques known to one skilled in the art of orgainc synthesis and further described in this invention.
Compounds wherein W is xe2x80x94C(R25)(R26)SC(R27)(R28)xe2x80x94, xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)C(R27)(R28)xe2x80x94 and xe2x80x94C(R25)(R26)S(xe2x95x90Zxe2x80x2)2C(R27)(R28)xe2x80x94, n is 1, and Zxe2x80x2 is defined above can be synthesized as shown in Scheme 12. Asymmetric epoxidation of muconic acid (Sharpless et al., J. Org. Chem. 57, 2768 (1992)); followed by benzylation (Seebach, D. and Wasmuth, D. Hely. Chim. Acta 63, 197 (1980)) provides a secondary diol, which can be converted to primary diol (XXXVIIa) by protection and reduction with lithium aluminum hydride. Further elaboration by the methods of Dugger et al. (Tetrahedron Letters 33, 6763 (1992)) and Trost et al. (Tetrahedron Letters, 22, 1287 (1981)) provide the sulfoxide shown. Further oxidation using a stronger oxidizing agent such as m-chloroperbenzoic acid would provide the corresponding sulfone (W is xe2x80x94C(R25)(R26)S(xe2x95x90O)2C(R27)(R28)xe2x80x94). The intermediates described therein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.
Compounds wherein W is xe2x80x94C(R25)(R26)C(xe2x95x90Z)C(R27)(R28)xe2x80x94, n is 1, and Z is defined above can be synthesized as shown in Scheme 13. Compound XXXVIIa could be converted to the corresponding dibromide using carbon tetrabromide/triphenylphosphine. Dithiane anion, formed according to the method of Seebach, as reported in Org. Syn., Coll. Vol. 6, 316 (1988), could be alkylated with this dibromide. The seven-membered ring ketone (Z is O), upon liberation with aqueous mercuric ion, could be alkylated according to methods reported in the literature. Imines (Z is NR24) and thiocarbonyls (Z is S) can be prepared by one skilled in the art of organic synthesis using methods described in the literature.
Compounds wherein W is xe2x80x94C(xe2x95x90Z)xe2x80x94, n is 1, and Z is defined above can be synthesized as shown in Scheme 14. Secondary diol (VII) could be converted to the dibromide using such as described previously. Dithiane alkylation followed by deprotection with mercury ion would produce the five-membered ring ketone. Alkylation of the alpha-carbons would provide for substitution at R4A and R7A. Thiocarbonyls and imines of the carbonyl could be prepared using methods described in the literature.
Compounds wherein W is xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)N(R23)xe2x80x94 or xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)Oxe2x80x94 and n is 1, could be prepared as shown in Scheme 15. Aminoalcohol (VIII) could be converted to the corresponding bromide using the method of Morin and Sawaya (Synthesis, (1987), 479) and displaced with lithiophosphinate according to the method of Corey and Kwiatkowski (J. Amer. Chem. Soc., (1966), 88, 5654). Deprotection of the amine protecting group would be followed by phosphoramide formation according to the method described by Patel et al., (Tet Lett., (1990), 31, 5591). Alkylation with strong base would lead to the compounds where W is xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)N(R23)xe2x80x94. Similarly, diazotization and nucleophilic displacement with hydroxide would lead to the compounds where W is xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)Oxe2x80x94 after cyclization.
Compounds wherein W is xe2x80x94C(R25)(R26)P(xe2x95x90O)(R24a)C(R27)(R28)xe2x80x94 or xe2x80x94P(xe2x95x90O)(R24a)xe2x80x94 and n is 1, could be prepared as shown in Scheme 16. Secondary diol (VII) could be brominated by the method of Morin and Sawaya to give (XXXVIa), which could be elaborated to (XXXVIIIa) via earlier described (XXXVIIa). Grignard coupling with methyl dichlorophosphate using the method of Polniaszek and Foster (J. Org. Chem., 1991, 56, 3137) would lead to a cyclic phosphinate. Alkylation with strong base based on methods described in the literature (ie., see Polniaszek above) would provide the desired products.
Compounds of formula (I) wherein W is xe2x80x94(R22)N+=C(R36)N(R23)xe2x80x94 and xe2x80x94N=C(R36)N(R23)xe2x80x94 and n=1 can be prepared according to Scheme 17. Intermediate (XXXIXa) can be cyclized under standard amidine reaction conditions, based on method known in the art. Quaternary salt formation with alkyl halide leads to compounds of the formula (XXXIXd) and (XXXIXe), which can be acid-deprotected according to method described herein.
Synthesis of intermediate (XLa) is described in Scheme 18a, and use thereafter is described in Schemes 18b-18c. N-Cbz-Phenylalaninal (XLbxe2x80x2) is prepared from optically-active phenylalanine (XLaxe2x80x2) by the route previously described. Compound (XLcxe2x80x2) can be prepared by the reaction of (XLbxe2x80x2) with an appropriate acetic acid anion equivalent such as a Reformatsky reagent derived from ethyl bromoacetate (prepared from bromoethyl acetate and zinc metal). Other acetic acid Ad anion equivalents are contemplated and are recognized by those possessing skill in the art. Compound (XLdxe2x80x2) can be prepared by reacting (XLcxe2x80x2) with an acyl anion equivalent such as a dithiane anion (such as that derived from 1,3-dithiane upon reaction with butyllithium). Other acyl anion equivalents are contemplated and are recognized by those possessing skill in the art. The conversion of (XLcxe2x80x2) to (XLdxe2x80x2) can also incorporate the use of either or both oxygen-protecting groups and nitrogen-protecting groups. A suitable oxygen-protecting group is the SEM (trimethylsilylethyloxymethyl) ether and a suitable nitrogen-protecting group is the Cbz (carbobenzyloxy) carbamate. Other protecting groups are contemplated including those described in Protecting Groups in Organic Synthesis, Second Edition by T. W. Greene and P. G. M. Wuts, John Wiley and Sons Inc., 1991. Compound (XLa) can be obtained by the hydrolysis of (XLdxe2x80x2) with acid or base.
Alternatively, (XLa) can be obtained as follows: (XLexe2x80x2) can be prepared by reaction of (XLbxe2x80x2) with a pyruvic acid anion equivalent such as a Reformatsky reagent. Other pyruvic acid anion equivalents are contemplated and are recognized by those possessing skill in the art. (XLfxe2x80x2) is prepared by the reaction of (XLexe2x80x2) with an alkyl or aryl derived nucleophile such as a Grignard reagent or an organolithium reagent (such as benzylmagnesium bromide or phenyllithium). Other organometallic species are contemplated and are recognized by those possessing skill in the art. Intermediate (XLa) can be obtained by reaction of (XLfxe2x80x2) under hydrolytic conditions needed to induce ester cleavage and/or conditions necessary to remove any or all protecting groups.
Intermediates (XLa)-(XLk) can be derived from (L)-phenylalanine, for example, although all other naturally-occurring and other unnatural amino acids are also contemplated.
Intermediate (XLb) can be prepared by the reaction of a methylene chloride solution of compound (XLa) with SEM-C1 (trimethylsilylethyloxymethyl chloride) in the presence of an amine base (such as diisopropylethylamine). Intermediate (XLc) can be obtained by the reaction of (XLb) with a carboxylic acid activating reagent such as dicyclohexylcarbodiimide (DCC). Other peptide-forming conditions and reagents are contemplated and are recognized by those possessing skill in the art. Intermediate (XLd) can be obtained by the reaction of (XLc) with an appropriately protected (if needed) hydroxymethylbenzyl halide followed by the removal of the SEM protecting groups via reaction with fluoride ion (tetrabutylammonium fluoride) in a suitable solvent (tetrahydrofuran).
Intermediate (XLe) is obtained by the reaction of (XLa) with SEM-C1 under conditions to avoid/suppress bis-alkylation such as limiting molar equivalents of SEM-C1 and/or using lower reaction temperatures. Intermediate (XLf) can be obtained reaction of (XLe) with phosgene in the presence of a suitable base. Phosgene equivalents and various amine bases are also contemplated and are recognized by those possessing skill in the art. Compounds of the formula (XLg) can be obtained by the same methodology described above for the preparation of (XLd) from compound (XLc).
Compounds (XLh) can be obtained by reacting (XLb) with Cbz-C1 (carbobenzyloxy chloride) in the presence of a base. Intermediate (XLi) can be obtained by reacting (XLh) with a carboxylic acid activating reagent in the presence of an amine such as ammonia. Other methods are contemplated and are recognized by those possessing skill in the art. Compound (XLj) is-obtained by the reaction of (XLi) with a carbon monoxide equivalent such as phosgene in the presence of an amine base as previously described for the conversion of (XLe) to (XLf). Compounds of the formula (XLk) can obtained by N-alkylation and removal of protecting group(s) as described for the conversion of (XLc) to (XLd).
A more detailed description of the general formulas is provided in Scheme 18c.
Compounds such as lactam (XLIm) with an alkoxy substituent could be synthesized as shown in Scheme 19. The alcohol (XLIh) obtained using the procedure of S. Thaisrivongs, et al (J. Med. Chem. 1991, 34, 2344-2356) can be alkylated with benzyl bromide using standard procedures to give (XLIi). Treatment with catalytic p-toluene-sulfonic acid in methanol cleaves the oxazolidine to give the free alcohol (XLIj) which can be then converted to the acid (XLIk) using the procedure described by S. Thaisrivongs, et al (J. Med. Chem. 1991, 34, 2344-2356). Protection of the alcohol as the t-butyldimethylsilyl ether and cyclization to the lactam is analogous to that described in Scheme 23.
Compounds such as the cyclohexane fused 7-membered ring lactam (XLIIh) could be synthesized as outlined in Scheme 20. The acid (XLIIa) is obtained following the procedure of J. A. Martin and G. J. Thomas (EP 0 512 343 A2). This can be treated with methanol and catalytic p-toluenesulfonic acid to give the free alcohol which can be protected as the t-butyldimethylsilyl ether to give the acid (XLIIc). The cyclization to the fused lactam (XLIIf) followed by an alkylation deprotection sequence can lead to (XLIIh)
Compounds of formula (XLIII) can be converted to a variety of cyclic structures and the general outline of useful routes is detailed in Schemes 21, 21a and 21b. Advanced intermediates (XLIIIh) and (XLIIIn) are known and details of their preparation are described in WO9301166-A (published 21 January 1993), herein incorporated by reference. The conversion of (XLIIIa) via known methodology and that described herein, to a 6-memebered cyclic structure (XLIIIg), wherein P denotes a suitable hydroxyl protecting group (for example 2-(trimethylsilyl)ethoxymethyl (SEM), 2-methoxyethyl (MEM)) and X can be NH, O. R and Rxe2x80x2 are similar to R4 and R7. Further alkylation of the nitrogens can be performed. Conversion of (XLIIIh) to a 7-membered cyclic structure via known synthetic transformations is described, wherein P denotes a suitable protecting group (for example SEM, MEM) and R and Rxe2x80x2 are similar to R4 and R7. X and Xxe2x80x2 can be any nucleophile (nucleophilic carbon, nitrogen, oxygen, sulfur). Conversion of intermediate (XLIIIn) to an 8-membered cyclic structure (XLIIIs) is described. P denotes-an appropriate protecting group; R and Rxe2x80x2 are similar to R4 and R7 and X can be any nucleophile; Xxe2x80x2 can be NH, O.
Compounds such as the benzo-fused 7-membered ring lactam (XLIVh) can be synthesized as outlined in Scheme 22. The acid (XLIVa) is obtained following the procedure of M. Hammond and S. W. Kaldor (EP 0 526 009 A1). The free alcohol can be protected as the t-butyldimethylsilyl ether to give the acid (XLIVc). The cyclization to the fused lactam (XLIVf) followed by an alkylation deprotection sequence can generate (XLIVh) by analogy to that described for Scheme 23.
Compounds of Formula (I) wherein, W is N(R22)C(xe2x95x90O)C(R27)(R28), n is 0 and R7 is hydrogen, and R4 and R27 are benzyl can be synthesized according to Scheme 23. Conversion of N-Boc-phenylalanine by an 8 step procedure can give intermediates of the formula (XLVa). Hydrolysis of the lactone, followed by activation of the acid functionality using methods known in peptide chemistry, followed by deprotection of the amine protecting group and intramolecular cyclization can give lactam (XLVe). Standard alkyation and alcohol liberation provide compounds of the formula stated above.
The preparation of compounds of the formula (XLVId) is shown in Scheme 24. The Wittig product from the first step is reduced to the allylic alcohol using DIBAL-H in methylene chloride at xe2x88x9278xc2x0 C. This alcohol can be epoxidized using m-chloroperbenzoic acid or using Sharpless epoxidation methodology to give the epoxy alcohol (XLVIa). The epoxide can be opened selectively using TMSN3 (Sharpless, K. B. J. Org. Chem (1988) 53 5185) to give the desired 1,2-diol. Exhaustive silylation followed by selective deprotection of the primary silyl ether gives compound (XLVIb). Standard primary tosylate formation followed by displacement with sodium azide can give the diazide (XLVIc). Reduction of the diazide using catalytic hydrogenation and cyclization using carbonyl diimidazole would give the 6-membered cyclic urea. Alkylation as described herein and deprotection would give the final product (XLVId). The diazide (XLVIc) can be manipulated to give a variety of cyclic structures as previously shown.
Compounds of the formula (I), wherein W=xe2x80x94R22NC(xe2x95x90O)NR23xe2x80x94, n is 1, R5 is OH or xe2x95x90O and R6=R6a is fluorine, can be synthesized as shown in Scheme 25. Compound (XLVIIa) can be oxidized to the corresponding ketone by Jones oxidation (Org. Syn. Coll., Vol. V, 866) followed by reaction of the carbonyl with a fluorinating agent such as DAST. Deprotection, cyclization, alkylation and removal of hydroxyl protecting groups (such as MEM) can give (XLVIIg), which can be further oxidized to (XLVIIh) using the method of Gallina and Giordano (Synthesis 1989, 466).
The preparation of compounds of the formula (XLVIIIc) is shown in Scheme 26. Starting from the known hydroxy ketone (XLVIIIa) (WO 92/00956, published Jan. 23, 1992) the alcohol can be protected and the amine function deprotected to give diamine (XLVIIIb). Cyclization and introduction of the R22 and R23 can be accomplished as described herein. Reduction of the ketone and deprotection can give the desired diol (XLVIIIc). Hydroxy ketone (XLVIIIa) can be converted to the triol (XLVIIIe). After alcohol protection, a second hydroxyl group can be introduced a to the ketone using standard chemical procedures known to one skilled in the art. After protecting this hydoxyl, the amines can be deprotected to give diamine (XLVIIId).
Using similar chemistry as discussed previously, the triol (XLVIIIe) can be prepared as shown in Scheme 26a. The mono-ol (XLVIIIj) can be prepared starting from the aldehyde (XLVIIIf) and an organometallic reagent (XLVIIIg). Both of these compounds can be prepared from amino acids using standard chemical procedures known to one skilled in the art. The alcohol (XLVIIIh) can be protected and manipulated as discussed previously to give the desired mono-ol (XLVIIIj).
The cyclic carbonates of the formula (XLIXb) can be prepared, as shown on Scheme 27, starting from commercially available 3,4-O-Isopropylidene-D-mannitol. Primary tosylate formation and base treatment can provide the diepoxide which can be opened with numerous nucleophiles to give compounds of the formula (XLIXa). Cyclization and deprotection would give the desired diol (XLIXb).
Compounds wherein W is xe2x80x94N(R22)P(O)(R24a)N(R23)xe2x80x94, n=1 and R24a is phenoxy or OH, can be synthesized as described earlier and as shown in Scheme 28. Diamine III could be cyclized with phenyldichlorophosphate using the method of Patois et al. (Heteroatom. Chem. 1990, 1, 369) to give the cyclic phosphoric amide. Alkylation with strong base and removal of the protecting groups using methods known to one skilled in the art would give the desired products.
Compounds of the formula (I) wherein W is xe2x80x94N(R22)C(xe2x95x90O)N(R23)xe2x80x94, and R22 and R23 are NH(R22a) and NH(R23a), respectively, can be prepared as shown in Scheme 29. Intermediate (XXIc) can be treated with chloramine to yield dihydrazine (LIa) according to the method of S. R. Sandler and W. Karo (Organic Functional Group Preparations, Vol 1, Academic Press, N.Y., 1983, p. 445), herein incorporated by reference. Cyclization using phosgene can give cyclic urea (LIb). Standard procedure for alkylation and deprotection can provide alkylated dihydrazine (LIc). Alternatively, (XXIc) can be treated with chloroaminobenzene, according to the method of S. R. Sandler and W. Karo above, to yield dihydrazine (LId). Cyclization using phosgene, followed by alkylation of the product as described previously, can provide compounds of the formula (LIe).
Compounds of the formula (I), wherein W is xe2x80x94N(R22)C(xe2x95x90C(CN)2)N(R23)xe2x80x94 and n=1, can be prepared as shown in Scheme 30. Intermediate (XXIc) can be treated with 1,1xe2x80x2-bismethylthio-2,2xe2x80x2biscyanoethylene in acetonitrile, followed by the standard procedure of alkylation and deprotection to give compounds of the formula (LIIa).
Compounds of the formula (I), wherein W is xe2x80x94N(R22)C(xe2x95x90S)N(R23)xe2x80x94, R22 and R23 are not hydrogen, and n=1, can be prepared as shown in Scheme 31. Mono-alkylated intermediate (XXVIIb) can be further reacted with a alkyl bromide under refluxing reaction conditions (to facilitate the removal of byproduct methyl bromide) to give dialkylated thiocarbonyl compound (LIIIa), which can be acid-deprotected as described previously.
Compounds of the formula (I), wherein W is xe2x80x94N(R22)C(xe2x95x90O)C(R27)xe2x80x94, n=1, and R28 and R7a are taken to form a bond can be prepared as shown in Scheme 32. The aldehydes required for coupling can be prepared by methods known to one of skill in the art. Acetylation after coupling can provide diacetate (LIVa). Amine protecting group modification can lead to (LIVb), afterwhich liberation of the carbonyl (LIVb) and Wittig olefination using stabilized Wittig can provide (LIVc), after separation of the geometric isomers. Liberation of the amine protecting group can provide (LIVd), which upon modification of the ester for standard amino-acid type coupling (via LIVe) can lead to compounds of formula (LIVf).